World Stem Cell Report Regen. Med. 7(6 Suppl.) (2012) ISSN 1746-0751
Closing the translational gap
Envision. Empower. Engage. Realize the potential. The science embraced. Therapies delivered. Whether your work is in research, translational medicine, advocacy, finance, regulation or policy, you want to see the promise of stem cell science materialize. Genetics Policy Institute (GPI), with a decade of advocacy behind it, continues to champion research, foster collaborations and promote educational and public initiatives that will enable regenerative medicine efforts to develop and flourish. Through our collective impact, we’ll bring the cures.
Embolden the field. GPI works with leading organizations, companies and individuals to coalesce and strengthen the advocacy community, remove barriers to progress and develop translational pathways. Along with other non-profits such as the Alliance for Regenerative Medicine, International Translational & Regenerative Medicine Center, Stem Cell Action Coalition – and many academic and governmental institutions – GPI catalyzes a worldwide effort to build support and momentum for the field. GPI produces the World Stem Cell Summit, an international forum for sharing knowledge, addressing challenges and heralding achievement. Authors newsletters. Launches legal and policy briefs. Cultivates media relations. And educates and mobilizes the public. All of which adds a powerful voice to the work that you do.
Connect with us. Because you and your organization care about the vitality and progress of regenerative medicine, you’ll want to join forces with GPI. Let us support your efforts. Contact GPI today: www.genpol.org
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World Stem Cell Report
Contents
Closing the translational gap
Introduction 1
Welcome to the World Stem Cell Report B Siegel
3
Research & Development
4
Research Spotlight
Interviews 8
StemCells, Inc.: clinical trials of stem cell therapies for CNS disorders M McGlynn
12
Bioengineered vascular graft with autologous stem cells: first use in the clinic M Olausson
Research Updates 17
Key developments in stem cell therapy in cardiology IH Schulman & JM Hare
26
Stem cells and neurodegenerative diseases: where is it all going? RA Barker
32
Ophthalmologic stem cell transplantation therapies TA Blenkinsop, B Corneo, S Temple & JH Stern
41
From cellular therapies to tissue reprograming and regenerative strategies in the treatment of diabetes C Ricordi, L Inverardi & J DomĂnguez-Bendala
Expert Focus 50
Convergence of gene and cell therapy A Bersenev & BL Levine
Contents continued overleaf...
Regenerative Medicine 7(6 Suppl.) (2012)
Regenerative Medicine Editorial Board The Editorial Board is drawn from the leading forces in regenerative medicine Senior Editor Chris Mason, University College London, UK
Associate Editors
Robert Lanza, ACT, CA, USA Phillipe Menasché, Hôpital Européen Georges Pompidou, FRA Gail K Naughton, Histogen Inc., CA, USA Glyn Stacey, UK Stem Cell Bank (NIBSC), UK
Editorial Advisors
Ali R, University College London, UK Adams G, Univ. of Southern California, CA, USA Allsopp T, Pfizer, USA Andrews PW, Univ. Sheffield, UK Anversa P, New York Medical College, NY, USA Atala A, Wake Forest University School of Med., USA Barker R, Cambridge Centre for Brain Repair, UK Bauer SR, Food and Drug Administration, USA Benvenisty N, Hebrew University of Jerusalem, IS Bertram T, Tengion, Inc., NC, USA Brüstle O, Bonn University, Germany Buckler L, Cell Therapy Group, CA Caulfield T, Univ. Alberta, CAN Chaudhuri J, University of Bath, UK Cheng L, Johns Hopkins University School of Med., USA Chuang AT, Harvard, MA, USA Dalton S, University of Georgia, GA, USA Dandashi F, FutureMed Company Ltd, SA De Bari C, Univ. Aberdeen, UK du Moulin GC, Genzyme Biosurgery, USA Dunnett S, Univ. Cardiff, Wales, UK Garry DJ, UT Southwestern Medical Center, TX, USA Genbacev O, Univ. California San Francisco, USA Hayek A, UCSD Whittier Institute, CA, USA Hirschi KK, Baylor College of Medicine, USA Itskovitz-Eldor J, Technion, IS Ilic D, King’s College London, UK Itescu S, Columbia University, TX, USA Jorgensen C, Lapeyronie Hospital, FR Kaplan B, Ben’s Stem Cell News, USA Keirstead HS, Reeve-Irvine Research Center, CA, USA Kemp P, Intercytex, UK Kloner R, Good Samaritan Hospital (USC), USA Knoepfler PS, University of California Davis, USA Koliatsos V, Johns Hopkins Uni. School of Med., USA Krtolica A, StemLifeLine, Inc., CA, USA Lako M, Univ. Newcastle, UK Lawford-Davies J, Clifford Chance, UK Laurencin C, MIT, MA, USA Lebkowski J, Geron, CA, USA Lewis A, Juvenile Diabetes Research Found., NY, USA L’Heureux N, Cytograft, USA Li R-K, Toronto General Hospital, CAN MacKay G, Organogenesis, MA, USA Madeddu P, Bristol Heart Institute, UK Martino G, San Raffaele Hospital, Italy McNeish JD, Pfizer Global R&D, USA Miller RH, Case School of Medicine Cleveland, OH, USA Oreffo R, Univ. Southampton, UK Patel A, McGowan Inst. for Regenerative Med., USA Penn MS, Cleveland Clinic Foundation, OH, USA Polak JM, Imperial College London, UK Rao M, Invitrogen Rowley JA, Lonza Cell Therapy, MD, USA Russell AJ, McGowan Inst. for Regenerative Med., USA Sachlos E, McMaster Univ., CAN Salter B, King’s College London, UK Sanberg P, USF Coll. of Med., FL, USA Scharfmann R, INSERM, FR Sharpe P, King’s College, London, UK Siegel B, Genetics Policy Institute Sipp D, RIKEN, JP Snyder EY, The Burnham Institute, USA Soria B, Andalusian Ctr Mol Biol and Regen Med, Spain Surani A, University of Cambridge, UK Sussman M, SDSU Heart Institute, CA, USA Terzic A, Mayo Clinic, MN, USA Trounson A, CIRM, USA Waldman SA, Thomas Jefferson University, PA , USA West M, BioTime, CA, USA Wilson IA, GE Healthcare Medical Diagnostics, UK Yoon Y-S, Tufts University School of Med., USA Young L, University of Nottingham, UK Zupanc G, Northeastern University, MA, USA
Contents cont.
57 Industry, commercialization & collaboration 59
Opinions 94
Autologous cell therapies: challenges in US FDA regulation TN McAllister, D Audley & N L’Heureux
100
Autologous cell therapies: the importance of regulatory oversight M Werner, T Mayleben & G Van Bokkelen
105
Pay-to-participate funding schemes in human cell and tissue clinical studies D Sipp
Industry highlights D Ilic
Interviews 64
Researchers and the translational reality K Aboody
69
The Regenerative Medicine Coalition F-R Lauter
Commentary 71
Collaborations in stem cell science J Thomas
Organization Profile 74
The International Translational Regenerative Medicine Center M de Veuve Alexis, K-H Grinnemo & R Jove
77 Policy, Regulation & Ethics 78
84
89
Perspective
113 Advocacy & Education Interviews 114
The making of an advocate A Fernandez
117
The New York Stem Cell Foundation S Solomon
Commentary 120
Why the stem cell sector must engage with social media L Buckler
Commentaries
125 Around the World
Regulation, manufacturing and building industry consensus R Deans
126
USA KRW Matthews & ML Rowland
132
Canada L Willemse, U Ogbogu, S Johnson & M Rudnicki
136
UK E Culme-Seymour
140
Sweden O Hovatta
144
Brazil R Mendez-Otero & AC Campos de Carvalho
Alliances, collaborations and consortia: the International Stem Cell Forum and its role in shaping global governance and policy R Isasi Cell standardization: purity and potency BJ Wagner
Global Updates
All World Stem Cell Report 2012 content is available free from the Future Medicine website at www. futuremedicine.com/loi/rme Indexing: Medline/Index Medicus, Science Citation Index Expanded, Biotechnology Citation Index®, Journal Citation Reports, Biological Abstracts, BIOSIS Previews, EMBASE/Excerpta Medica, Chemical Abstracts Impact factor: 3.718 (2011)
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Florence, Italy Stem Cells in Translation September 15 –18, 2013 Palazzo dei Congressi
Florence Italy www.isscr.org/Conference_Series.htm
2013 Conference Series
SUZHOU CHINA Suzhou, chIna Stem Cells in Science and Medicine october 14 –18, 2013 Dushu Lake Hotel and Conference Center
www.isscr.org/Conference_Series.htm
Welcome to the
World Stem Cell Report Message from Bernard Siegel, Founder and Editor-in-Chief, World Stem Cell Report, Executive Director of Genetics Policy Institute and Founder and Co-chair, World Stem Cell Summit
“
Our 2012 World Stem Cell Report aims to provide ‘actionable intelligence’ to the community as part of our mission to enhance societal support, facilitate collaborations and accelerate the march to cures...
”
When the Genetics Policy Institute (GPI) launched the World Stem Cell Report in 2008, it was to fill an unmet need. We sought to create a new publication in print and made available digitally that would serve as an accessible benchmark and progress report for the emerging field of regenerative medicine, a tool for understanding the global, societal context to the expanding stem cell ‘multiverse’. GPI has monitored the field since 2003, and 9 years later we find ourselves immersed in a ‘Cambrian Explosion’ of diversity of rich new research data, new commercial ventures, new global collaborations and alliances. Our 2012 World Stem Cell Report aims to provide ‘actionable intelligence’ to the community as part of our mission to enhance societal support, facilitate collaborations and accelerate the march to cures. We explore the nooks and crannies of our burgeoning field by examining trends, shining light onto the controversies and offering balance, inspiration and unique perspectives delivered by an array of international authorities who are experts in their respective disciplines. The Report serves as a roadmap to regenerative medicine in all its aspects; Research & Development, spotlighting several key disease categories; Industry, Commercialization & Collaboration, providing our annual industry review with a focus on business development and clinical trials and translational challenges; Policy, Regulation & Ethics, where we include opinion pieces and commentary relating to the role of the US FDA and others in regulating autologous stem cell treatments and the critical need for cell standardization; in the section relating to Advocacy & Education, we provide the insights of leading advocates; and, finally, in the section Around the World, we take a country and regional look at stem cell centers around the globe, focusing on the USA, Brazil, Sweden, Canada and the UK. Our 2012 World Stem Cell Report is a supplement to the award-winning Medlineand ISI-listed journal Regenerative Medicine (2011 impact factor: 3.7). As a peerreviewed publication, the Report reaches a global audience that includes all the attendees of the 8th Annual World Stem Cell Summit in West Palm Beach, Florida, USA 3–5 December. The Summit is produced by the GPI and co-organized with the Interdisciplinary Stem Cell Institute (ISCI) of the University of Miami Miller School of
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Medicine, Diabetes Research Institute, Beckman Research Institute at City of Hope, Karolinska Institute (home of the Nobel Prize in Physiology or Medicine), International Translational Regenerative Medicine Center (ITRC) and the Kyoto University Institute for Integrated Cell-Material Sciences (iCeMS). We believe the Report contributes to the collective mission of these wonderful co-organizing institutions and the goals of those assembled for the Summit. I again thank my esteemed colleagues, Professor Chris Mason, Senior Editor of Regenerative Medicine; Elisa Manzotti, Charlotte Barker and the rest of the Future Medicine team for their indispensable contributions to the Report. Societal context and clarity are weapons in the arsenal targeting disease. We must all remember that these powerful technologies discussed in the Report hold the promise of delivering actual cures and thus alleviating so much human suffering. This is a mighty quest, a huge lift and an exciting journey. The world awaits. Let’s work together to reach our collective goals! Cordially,
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ADVOCACY & EDUCATION
Article type
RESEARCH & DEVELOPMENT
research spotlight Interviews StemCells, Inc.: clinical trials of stem cell therapies for CNS disorders Martin McGlynn Bioengineered vascular graft with autologous stem cells: first use in the clinic Michael Olausson
research Updates Key developments in stem cell therapy in cardiology Ivonne H Schulman & Joshua M Hare Stem cells and neurodegenerative diseases: where is it all going? Roger A Barker Ophthalmologic stem cell transplantation therapies Timothy A Blenkinsop, Barbara Corneo, Sally Temple & Jeffrey H Stern From cellular therapies to tissue reprogramming and regenerative strategies in the treatment of diabetes Camillo Ricordi, Luca Inverardi & Juan Domínguez-Bendala
Expert focus Convergence of gene and cell therapy Alexey Bersenev & Bruce L Levine 10.2217/RME.XX.XX © 2011 Future Medicine Ltd
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RESEARCH & DEVELOPMENT RESEARCH & DEVELOPMENT
Research Highlights
RESEARCH SPOTLIGHT Highlighting some of the year’s the most important advances in regenerative medicine and stem cell research
Pioneering surgery uses bioengineered vein produced with patient’s own stem cells 2012 saw a world first, when surgeons at Sahlgrenska University Hospital in Sweden used stem cells to grow a replacement blood vessel for a 10-year-old girl. The child developed a blood clot in a major blood vessel to her liver, a condition that can cause serious complications and if not treated can lead to a liver transplant being required. Normally, surgeons aim to correct the problem by replacing the damaged vessel with one from another part of the body. However, in this case that proved impossible so the team went to their Plan B – a tissue engineered blood vessel using the patient’s own cells. A deceased donor vein was stripped of all its cells to produce a scaffold, onto which the girl’s bone marrow stem cells were seeded Despite the premature halt of Geron’s trial of hESC-derived cells for and differentiated to form a new blood spinal cord injury late last year, both basic and clinical research continued vessel. The patient is doing well following to develop in this field during 2012. the transplant. StemCells, Inc., using their human neural stem cell product, reported The surgeon who carried out the preliminary data from their spinal cord injury trial in May and again procedure, Professor Michael Olausson, in September 2012. To date, three patients with thoracic spinal cord told Regenerative Medicine “I have been injuries have been treated. None of the patients have suffered any major involved in transplantation related research adverse effects from the surgery or the cells themselves. While the trial since I first started medical school in is predominantly focused on safety, two of the three patients have 1975. And in my view this is, without any shown measurable improvements in sensory function (response competition, the most interesting thing to heat, touch). The third patient has remained stable. that has happened during all these years. Meanwhile, Neuralstem, Inc, who already have a clinical “I think the use of tissue engineering and trial underway for amylotrophic lateral sclerosis (ALS), stem cells in this way is really exciting, and moved a step closer to clinical trials in spinal cord injury. we will see more exciting results in the next The company published research in September 2012 5-10 years than we did in 30 years before.” showing that rats with spinal cord injury injected You can read more in an interview with with the company’s human spinal cord cells Professor Olausson on page 12. (NSI-566) regained movement in previously paralyzed limbs. Source: Olausson M, Patil PB, Kuna VK et al.:
There’s life after Geron for stem cell treatments in spinal cord injury
Transplantation of an allogeneic vein bioengineered with autologous stem cells: a proof-of-concept study. Lancet 380(9838), 230–237 (2012).
– Written by Jonathan Wilkinson
– Written by Charlotte Barker 4
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Exciting developments in stem cell therapies to repair damaged retina
A topic that has been generating a huge amount of excitement throughout 2012 is stem cell-derived cell therapies to treat vision loss. In early 2012 the first trial using cells derived from human embryonic stem cells (hESCs) to treat two forms of blindness showed positive results regarding their safety and tolerability. The researchers reported that two patients, one with Stargardt’s macular dystrophy and the other with dry agerelated macular degeneration, showed improvements in their vision for up to 4 months after receiving the cell therapy. Importantly, no negative side effects were observed in the patients, with no signs of deterioration in their vision. The study was performed at the Jules Stein Eye Institute at the University of California (CA, USA), using cells developed by Advanced Cell Technology. Controlled differentiation of hESCs was used to produce retinal pigment epithelial cells, which could be transplanted into patients. The trial is now treating further patients with a higher dose of cells. Stem Cells, Inc have also launched a clinical trial in macular degeneration, in this case using purified human neural stem cells. The Phase I/II trial was approved by the FDA in January 2012 and the trial launched in June 2012 at Retina Foundation of the Southwest’s (RFSW) Anderson Vision Research Center in Texas, USA. StemCells Inc President & CEO, Martin McGlynn told Regenerative Medicine “In a rat model of macular degeneration, we have shown that neural stem cells can do some remarkable things, and effectively preserve vision, so we are very excited to be moving into clinical trials for AMD.” Read more in the full future science group
“
I think the use of tissue engineering and stem cells in this way is really exciting, and we will see more exciting results in the next 5–10 years than we did in 30 years before.
”
interview, on page 8. Advances are being made in the cornea as well. Scientists from the Sahlgrenska Academy at the University of Gothenburg (Sweden) used stem cells to regenerate a damaged cornea in the lab. The investigators successfully transplanted hESCs into damaged human corneas in vitro and found that they proliferated and differentiated into corneal epitheliallike cells. Although this research was performed in an in vitro model, the researchers are enthusiastic about what implications these findings may have in ophthalmology. Charles Hanson, lead author of the study, explained: “Similar www.futuremedicine.com
experiments have been carried out on animals, but this is the first time that stem cells have been grown on damaged human corneas. It means that we have taken the first step towards being able to use stem cells to treat damaged corneas.” Sources: Hubschman P, Heilwell G, FrancoCardenas V et al. Embryonic stem cell trials for macular degeneration: a preliminary report. Lancet doi:10.1016/ S0140-6736(12)60028-2 (2012) (Epub ahead of print); Hanson C, Hardarson T, Ellerström C et al. Transplantation of human embryonic stem cells onto a partially wounded human cornea in vitro. Acta Ophthalmol. doi:10.11 11/j.1755-3768.2011.02358 (2012) (Epub ahead of print). – Written by Jonathan Wilkinson
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A complex picture for bone marrow stem cells in heart disease Results published in the Journal of the American Medical Association and announced at the American College of Cardiology’s 61st Annual Scientific Sessions in Chicago (IL, USA) added new data to the question of whether the use of bone marrow-derived stem cells will one day be a suitable treatment for heart failure. Although the study failed to show a significant improvement on identified end points, a small improvement in ejection fraction was reported, especially in younger patients, leading to interesting insights regarding why certain populations respond better to stem cells. “We found that the bone marrow cells did not have a significant impact on the original end points that we chose, which involved reversibility of a lack of blood supply to the heart, the volume of the left ventricle of the heart at the end of a contraction and maximal oxygen consumption derived through a treadmill test,” reported Robert Simari from the Mayo Clinic in Rochester (MN, USA) and chairman of the Cardiovascular Cell Therapy Research Network, who coordinated the trial.
“
In a rat model of macular degeneration, we have shown that neural stem cells can do some remarkable things, and effectively preserve vision, so we are very excited to be moving into clinical trials for AMD.
”
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Despite this, the simple measure of ejection fraction – percentage of blood pumped from the left ventricle – was improved by 2.7% over placebo. This effect was larger in patients under the population’s average age of 63 years, with a 4.7% reported improvement over placebo. The
by researchers at Technion-Israel Institute of Technology in Haifa who successfully reprogrammed skin cells from heart failure patients into healthy cardiomyocytes. Not only did the cells fully differentiate into cardiomyocytes from human induced pluripotent stem cell, they also showed full integration into the existing heart tissue in rats. While the results are still a long way from any clinical application, Lior Gepstein, leader of the research group, is enthusiastic about the potential of the work: “What is new and exciting about our research is that we have shown that it’s possible to take skin cells from an elderly patient with advanced heart failure and end up with his own beating cells in a laboratory dish that are healthy and young – the equivalent to the stage of his heart cells when he was just born.”
researchers found that these patients has a larger fraction of CD34 + and CD133 + cells in their stored bone marrow cells, and these cells may become a possible target in the hunt for targets to improve the engraftment of stem cells in cardiac conditions. As well as bone marrow-derived adult stem cells, scientists are exploring a range of stem cell types for cardiac repair. Another cell type with clinical potential was identified Regen. Med. (2012) 7(6 Suppl.)
Sources: Perin EC, Willerson JT, Pepine CJ et al. Effect of transendocardial delivery of autologous bone marrow mononuclear cells on functional capacity, left ventricular function, and perfusion in chronic heart failure: the FOCUS-CCTRN trial. JAMA doi:10.1001/ jama.2012.418 (2012) (Epub ahead of print); Zwi-Dantsis L, Huber I, Habib M et al. Derivation and cardiomyocyte differentiation of induced pluripotent stem cells from heart failure patients. Eur. Heart J. doi:10.1093/eurheartj/ehs096 (2012) (Epub ahead of print). – Written by Louise Rishton
future science group
Hear it is: a possible cure for deafness? Scientists from the University of Sheffield (Sheffield, UK), demonstrated that human embryonic stem cellderived cells improved hearing in deaf gerbils. The gerbils had experimentally induced auditory neuropathy, a form of deafness that is caused by damage to the neurons that connect the brain to the sensory hair cells. In this study, the researchers induced human embryonic stem cells to differentiate into auditory neurons (otic neural progenitors) and hair cell-like cells (otic epithelial progenitors). The otic neural progenitors were then transplanted into the animals. It was demonstrated that 4 weeks after transplantation, there was a
46% average overall improvement in hearing. Project leader, Marcelo Rivolta, Centre for Stem Cell Biology, University of Sheffield, explained: “The responses of
the treated animals were substantially better than those untreated, although the range of improvement was broad. Some subjects did very well, while in others recovery was poor.” Even with the range of results, Rivolta was confident the findings provide potential for the future, and plans to continue the research to test the long-term effects and safety of the treatment. Source: Chen W, Jongkamonwiwat N, Abbas L et al. Restoration of auditory evoked responses by human ES-cell-derived otic progenitors. Nature doi: 10.1038/nature11415 (2012) (Epub ahead of print). – Written by Natasha Leeson
Nobel Prize in Physiology or Medicine 2012: Gurdon and Yamanaka John Gurdon (UK) and Shinya Yamanaka (Japan) have received the 2012 Nobel prize in physiology or medicine for the discovery that mature cells can be reprogrammed to become pluripotent.
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Their findings have allowed scientists a greater understanding of cell reprogramming and disease mechanisms…
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It was Gurdon’s 1962 discovery that the fate of specialized cells can be reversed that first opened the door to this new understanding of cell development. He was able to prove his revolutionary future science group
hypothesis by demonstrating that a frog egg developed into a functional cloned tadpole after he had substituted the cell nucleus of the frog’s egg cell with a nucleus from a mature, specialized cell of a tadpole. Over 40 years later, in 2006, Yamanaka was able to expand on this research and demonstrate that intact mature cells could be reprogrammed to pluripotency by a specific set of genes. By introducing varying combinations of these genes into mature cells, Yamanaka and colleagues discovered that a combination of four genes could reprogram the mature cells to immaturity. These induced pluripotent stem cells could then develop into a variety of mature cell types. www.futuremedicine.com
Their findings have allowed scientists a greater understanding of cell reprogramming and disease mechanisms and may even lead to the development of new therapies. If the next 40 years hold similar advances in knowledge, the future of stem cell research will be very exciting! Sources: Gurdon JB. The developmental capacity of nuclei taken from intestinal epithelium cells of feeding tadpoles. J. Embryol. Exp. Morphol. 10, 622–640 (1962); Takahashi K, Yamanaka S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126(4) 663–676 (2006); Nobel Prize press release: www.nobelprize.org/nobel_ prizes/medicine/laureates/2012/# - Written by Natasha Leeson
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RESEARCH & DEVELOPMENT
Interview StemCells, Inc.: clinical trials of stem cell therapies for CNS disorders
Interview with Martin McGlynn Martin McGlynn, President & Chief Executive Officer of StemCells, Inc., talks to Regenerative Medicine about the company’s ongoing clinical trials with their human neural stem cell treatment (HuCNS-SC®). Martin McGlynn joined StemCells, Inc. in January of 2001 as President and Chief Executive Officer, and was elected to its Board of Directors on February 6, 2001. Martin McGlynn has spent several decades as a senior executive in the life sciences industry in Europe, Canada and the USA. He began his career in Manufacturing Operations with Becton Dickinson, Ireland Ltd. then joined Abbott Labs in 1977 where he held positions as General Manager, Abbott Ireland Ltd, President and General Manager of Abbott Canada Ltd and Vice President of Abbott International Ltd. Martin McGlynn currently serves as a member of the Board of the Alliance for Regenerative Medicine and is co-Chairman of its Operations and Governance Committee.
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Tell us a little about the company’s approach to developing adult stem cell treatments. StemCells, Inc. takes an approach that we call homologous use of stem cells, meaning we take cells from brain tissue and put them back into the brain; we take liver cells and put those back into the liver; and we put pancreas cells back into the pancreas. We do it this way because we are working with adult stem cells. Unlike an embryonic stem cell, which can give rise to every cell type in the body (pluripotent), adult stem cells are essentially hard-wired to their specific organ system. For example, the cell type we are working with for CNS indications, human neural stem cells (HuCNS-SC®), are hard-wired to
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In all the transplants we have done (in thousands of animals and 13 patients), we have seen no evidence of tumorigenic activity…
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become the three main cellular actors of the CNS – neurons, astrocytes and oligodendrocytes – while maintaining a pool of stem cells for lifelong repair and replacement of these specialized cells of the CNS. The cells we use are unmodified – we do not genetically alter them. They are expandable to commercial scale in cell banks, so it is a business model that is focused on product development as opposed to a patient-by-patient service business. We can grow billions of cells in master cell banks and cryopreserve them ready to make patient products for transplant: these really are stem cells in a bottle. These cells are hard-wired to become only cells of the CNS, they can be directly transplanted as such and are
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believed to be nontumorigenic – they do not give rise to tumors (in vitro or in vivo). In all the transplants we have done (in thousands of animals and 13 patients), we have seen no evidence of tumorigenic activity, so the US FDA is increasingly comfortable with the safety profile of these cells being transplanted into humans. So what happens when you put these cells into a living host? They engraft, they migrate and then they differentiate into neurons, astrocytes or oligodendrocytes in a site-specific way. These cells take their cues from the host microenvironment and, depending upon the host organ, whether it is in the brain or spinal cord, they will predominately become one or another of the cells, and start carrying out the cells’ assigned function. This opens up a very broad spectrum for applications in the clinic. It is an amazing cell, it does amazing things when transplanted into animals, and we are now in the business of replicating what we’ve seen in human patients. What made StemCells, Inc. choose to explore an allogeneic rather than autologous approach? Put simply, allogeneic cells can be expanded into millions of cells, which you can then use to treat thousands of patients, whereas an autologous approach involves taking patient tissue, processing it in some way and then putting it back into the patient. It is more like a service or medical procedure than a product business model. In a liver transplant you transplant one patient from one donor. In the case of allogeneic therapies, it could be thousands of patients from one donor. The benefit of the autologous approach is that the patient recognizes the cells as self. So unless there is something done to the cells to alter them outside the body, the likelihood that they will be rejected when transplanted back into the donor is very low. With future science group
the allogeneic approach we use, where you take donor tissue and transplant it into a host, the host immune system will recognize the cells from donor tissue as foreign. So the immune system will immediately go about setting up defences, and in time would reject the donor cells. Therefore, when you are developing allogeneic transplant methodologies, you also have to develop immunosuppressant regimens. In the CNS, the immunosuppression is temporary: we stop the immuno suppressant regimen after 9 months because by that time it seems the cells have integrated into the body and the host has accommodated them. Importantly, we do know from trials we have done, the Batten disease study for example, that not only do the cells survive with the immunosuppressant regimen and do so for long periods of time, but the cells survive way beyond cessation of the immunosuppression. Could you give us an overview of the clinical trials that are underway at the company? We are the only company worldwide to my knowledge that has clinical trials underway in all three regions of the CNS – the brain, the spinal cord and the eye. All of these trials are using the same cells – HuCNS-SCs. The first clinical trial we did was in a fatal lysosomal storage disease, Batten disease. It was the first ever human neural stem cell transplantation. We transplanted over a billion cells into a human brain, with the aim of using the cells to deliver enzymes that were missing in the brains of these patients. We completed that Phase I study in January 2009. The results from the Phase I study were very promising. This is a progressive and invariably fatal disease, and the children being treated were at an advanced stage. Of the six transplanted patients, three of them are still alive today – two patients in the study are, more than 5 years after treatment. It is hard to go beyond that observation because it was not a controlled clinical study, but my www.futuremedicine.com
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The benefit of the autologous approach is that the patient recognizes the cells as self.
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opinion is that you cannot rule out the possibility that the cells have helped these surviving children. A Phase II trial was approved by the FDA, but could not be completed due to insufficient enrolment. The second study we launched was in Pelizaeus–Merzbacher disease (PMD), a fatal hypomyelination disorder. These patients have no myelin or very little myelin and are incapable of generating myelin. When the brain’s myelin is damaged or insufficient (hypomyelinated), the axons die and the patient dies in childhood. Here we are using the same neuronal stem cells to myelinate the host axons that are hypomyelinated. We completed the PMD trial in February of this year. We have announced top-line results and the detailed results of that study are under review in a peer-reviewed journal. All four patients undergoing transplantation in that study were shown to have no myelin on their nerve axons at baseline. Three of the four patients presented small but measureable improvement in neurological markers, while the fourth patient was clinically stable. This was a remarkable observation. Not only did the cells engraft and survive, but they are biologically active, and they appear to have conferred a clinical benefit to these patients. The next trial we initiated was in spinal cord injury, a Phase I/II trial being carried out in Switzerland and authorized by Swissmedic. Our study design means that we start off with the worst of the worst-affected patients, the ASIA A population who have no sensory or motor function below the level of injury. We have dosed all three ASIA-A patients in the first cohort, and have started enrolling the ASIA B’s, who have incomplete injury. We enroll patients 3–12 months postinjury. This makes it very different to the Geron study, which was enrolling patients within a couple of weeks of spinal cord injury. Our view is that if you put cells in too early they may not survive in what is a very hostile inflammatory environment, 10
and if there is an effect, good or bad, it is hard to know whether it is caused by the cells or by progression of the injury. We reported safety data in May of this year, showing a very good safety profile, and an exciting development is that two of the patients are reporting improved sensation to light touch below the site of injury. We plan to be in London, UK, in September to present data on the 6-month evaluation of these patients, which we are all looking forward to.
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We are the only company worldwide to my knowledge that has clinical trials underway in all three regions of the CNS – the brain, the spinal cord and the eye.
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The fourth trial is in age-related macular degeneration. We had a Phase I/II study authorized by the FDA in January 2012, and initiated the study in June 2012 at the Retina Foundation of the Southwest’s Anderson Vision Research Center in TX, USA. In a rat model of macular degeneration, we have shown that neural stem cells can do some remarkable things, and effectively preserve vision, so we are very excited to be moving into clinical trials for AMD. What new clinical trials do you hope to initiate over the next few years? We recently got a US$20 million award from the California Institute for Regenerative Medicine to initiate INDenabling activities for a trial in cervical spinal cord injuries, which occur a little further up the spine, closer to the neck. That is where the majority of spinal cord injuries occur. Our game plan is to initiate clinical trials within 4 years, by which time we should have data from the thoracic spinal cord injury clinical trial. In preclinical development is a very important program in Alzheimer’s Regen. Med. (2012) 7(6 Suppl.)
disease, for which we have again applied for funding of up to US$20 million for IND-enabling activities. What we have shown is that HuCNS-SCs are able to enhance memory in animal models of Alzheimer’s disease. And they do so independent of eradicting plaques and tangles. It is a very intriguing and controversial observation, especially because there has been little success clinically using strategies targeting plaques. The Batten and PMD trials enrolled children with genetic brain disorders. Are there any special challenges in conducting clinical trials in children? There are elevated regulatory and ethical considerations when you conduct any clinical trials in children. There is a heightened sense of scrutiny with regards to the risk–reward equation. Is there a body of evidence that suggests that it is reasonably safe to put these cells into children? And secondly, is there a likelihood that the children might benefit from the procedure? In the case of adults you certainly have to be able to demonstrate that it is reasonably safe, but the expectation in terms of the clinical benefit for the subject is not as high. The Batten disease program did not progress to a Phase II trial due to a lack of enrolment. Is enrolment likely to be problem for the PMD program? In the case of the first study, we put the cells into the worst-affected children – most of their neurons had already died so there was very little left to protect with our cells. So the purpose of the second study was to go into patients who had most of their neurons intact. That means we had to find them much earlier. What we found after 6 months of trying is that we could not identify a single patient who met the study criteria. The simple reason is that it takes our healthcare system too long to come up with the correct diagnoses for these children. Children future science group
Clinical trials of stem cell therapies for CNS disorders
with Batten disease for all intents and purposes look very healthy – there are no immediate tell-tale signs. Over time, the parents start to notice their children are not hitting developmental milestones and start to get seizures. But often the children are initially misdiagnosed and treated with seizure meds. It is only after the seizure meds do not control the disease that eventually somebody orders the diagnostic tests. It takes more than 2 years on average, by which time pathology is too severe and they have lost most of their neurons. So we were forced to shelve the program, not because we were not confident about the technology and the ability to help these kids, but until such a time as our healthcare system has addressed the problem and is able to diagnose much earlier. We are definitely open to re-intiating the trial if that situation does come about. We are in a state of watchful waiting. PMD is another rare disease but in children with the most severe form, connatal PMD, it is obvious from infancy that there is something wrong so these children are diagnosed very early. We even had a 14-month-old baby in our trial. So we should not have the same problem we had with Batten disease of identifying early-stage patients. How do you think the field of stem cell therapy will develop over the next 5–10 years? The field is maturing rapidly. The rate of progress in opening up clinical trials and advancing towards the clinic has accelerated exponentially. In the case of StemCells, Inc., over the next 3–4 years we will have human clinical data and results of clinical trials from the brain, the spinal cord and the eye. However, it is not an easy path to the clinic. I think the two biggest challenges facing the industry are being able to separate the good science from the bad and to sustain funding.
future science group
It is going to become more and more difficult to discern what is important and what is not, to separate the wheat from the chaff. It is always challenging for patients and their families, as well as investors, to cut through all the hype and figure out what is real. I can only speak for StemCells, Inc. and say we have done all the heavy lifting when it comes to the scientific premise, the preclinical data, and the rigor and design of our clinical trials. In terms of funding, there is a big question mark over who is going to fund companies engaged in translation through the ‘valley of death’ between proof of principle and the clinic. The venture capital community appears disinterested in the stem cell space and the public investor community is skittish, sceptical and confused. Ultimately, until such time as we have clinical data proving efficacy, it is going to be a struggle. Thankfully, in California, the California Institute for Regenerative Medicine is like the US cavalry as far as we are concerned: we have been waiting for them to come over the hill! They are certainly going to be a game changer in terms of helping companies like ours make it through the valley of death and come out the other side with human clinical data.
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…the two biggest challenges facing the industry are being able to separate the good science from the bad and to sustain funding…
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Financial & competing interests disclosure M McGlynn is a director and employee of StemCells, Inc. (“Company”), the sponsor of the preclinical and clinical studies described in the manuscript. The Company has previously disclosed, in SEC filings, press releases and other corporate communications, the clinical and preclinical information discussed in the manuscript. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
www.futuremedicine.com
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RESEARCH & DEVELOPMENT
Interview Bioengineered vascular graft with autologous stem cells: first use in the clinic
Interview with Michael Olausson Michael Olausson talks to Regenerative Medicine about the pioneering clinical use of a bioengineered vascular graft to treat a 9-year-old girl with extrahepatic portal vein obstruction and the future potential of bioengineered vessels.
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How did you first become involved in vascular tissue engineering? It started 5 or 6 years ago. I was at the American Society for Transplant Surgeons winter meeting in the USA, where some of the lectures dealt with tissue engineering. There was an intriguing talk about kidneys in pigs and later I heard about Doris Taylor’s work with tissue engineered hearts. Those two lectures fascinated me and really sparked my interest in the field of tissue engineering. What are the key research activities your group is currently engaged in? We have two main projects: one involves the synthesis of vascular blood vessels, such as arteries and veins, and the other on airways. Those are the two main fields that we’re currently engaged in. Your research group has received a lot of media attention recently concerning the implantation of a donor vein that was bioengineered with autologous stem cells to treat
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a young girl with extrahepatic portal vein obstruction. What led to this particular patient being selected for the new procedure? The patient was 9 years old at the time of diagnosis, which is very late for thrombosis of that particular vessel. There was uncertainty as to whether the patient was a candidate for traditionally used methods: either using an open umbilical vein or the jugular veins. These methods were plan A but we were concerned that the patient’s own vessels were on the short side. Therefore, we asked for permission to use the bone marrow stem cells from the girl to produce a bioengineered vessel, to provide a back-up option. As it turned out, plan A proved problematic, so therefore we used our plan B, the bioengineered vessel.
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The actual time to produce it [the vessel] was in the order of 3–5 weeks.
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It is really important to get the flow back because sooner or later the patient would be a candidate for a liver transplant, and that is a more risky procedure and costs a lot of money. These factors made this patient suitable to try the new technique, as compassionate use. How long did it taken to produce the implant? The actual time to produce it was in the order of 3–5 weeks, because you have to have a good source for the matrix and then collect the cells and so on. So it would not be the type of thing that you could use for an emergency procedure, only for elective or planned surgery. What was the outcome of the surgery for the patient? Well it was quite a dramatic change, as we would expect with the usual surgery. Before the surgery the parents will typically report that the child is tired, not performing in school, having difficulty in grasping the curriculum and are not reaching the goals that children their age are expected to.
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Bioengineered vascular graft with autologous stem cells: first use in the clinic
Michael Olausson has been Professor of Transplantation Surgery at Gothenburg University (Gothenburg, Sweden) since 2000, and was Chairman of the Sahlgrenska Transplant Institute at Sahlgrenska University Hospital (Gothenburg, Sweden) between 1994 and June 2011. His scientific interests include transplant immunology and experimental and clinical transplantation studies. He has published over 240 original articles, reviews and book chapters in the field of transplantation. He has been invited as a speaker at several national and international meetings all over the world. He has pioneered several innovative surgical procedures in the Nordic countries, Europe and the rest of the world. Last year, he performed the first operation in the world using a stem cell-derived vein and recently he performed the two first mother-to-daughter live donor uterus transplantations in the world, together with a team from Gothenburg. In the past, he has been President of The Swedish Transplantation Society, and board member and Vice President of the European Liver and Intestinal Transplantation Association. In 2008 he received the Carl-Gustav Groth Scandinavian Transplant Prize.
The parents of this patient reported almost immediately that they could see a difference; the girl was much more awake and active, and took part in games and in school work. We also noted a difference when the girl was in the hospital, that she was a lot more active and responded quicker.
bioengineered vessels on an everyday basis, and potentially for other kinds of vessels; it is challenge but I think it is possible. Hopefully, further operations and experiments will be successful and open up new opportunities. We are very intrigued by the result and it provides an important proof-of-concept.
There was a problem, which required the patient to have further surgery later on, but this was not, as far as we know, related to the bioengineered vessel. The vessel itself is good and it is now 6 months on from the second procedure, so I truly believe that it works.
Do you think that the use of bioengineered vessels will one day overtake existing techniques?
What are the main benefits & problems with this method compared with existing techniques? The main advantage is that it is almost a self-made product – it is as close as possible to a vein being made by a patient, the only thing different is the matrix. This means that the technique does not need any immunosuppressive drugs, as you would with a transplant from a donor. The downsides would mainly be the logistics of producing future science group
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I first started medical school in 1975. And in my view [the bioengineered vessel] is, without any competition, the most interesting thing that has happened during all these years.
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Yes, I think so. Especially when you use the existing method of transplanting one of the jugular veins, because it is disadvantageous to take away one of the very important veins for giving fluids, in case of emergency procedures. Especially with this specific operation, artificial grafts are not an option, they have too low patency. So you have to hope for an open umbilical vein, which may not always be available. In these cases it would be an advantage to have a tailor-made vessel, and not have to worry about finding a suitable vein in the patient to transplant. I am sure there will be more patients in the future who will be operated on www.futuremedicine.com
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using this technique, but of course you have to evaluate the method more carefully on a case-by-case basis. How does the bioengineered graft compare with standard procedures on cost? Of course it depends on where you start counting. If it is a choice between the bioengineered vessel or a liver transplant, this technique would save the health provider a lot of money. At least here in Sweden a liver transplantation costs approximately €70,000–80,000 and that is not counting the medications and all the other steps that the patient has to undergo before liver transplantation. It is also a procedure that carries a 10%
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mortality rate within the first year. On the other hand, if you compare using the bioengineered vessel with a successful procedure using the patient’s own vessels, the bioengineered vessel costs more. If you can show that the bioengineered vessel works, or even is more efficient, then I am sure it is cost effective. How do you expect the field of tissue engineered vascular grafts to develop over the next 5–10 years? I have been involved in transplantationrelated research since I first started medical school in 1975. And in my view this is, without any competition, the most interesting thing that has
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happened during all these years. I think the use of tissue engineering and stem cells in this way is really exciting, and we will see more exciting results in the next 5–10 years than we did in 30 years before.
Financial & competing interests disclosure The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
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RESEARCH & DEVELOPMENT
Research Update Key developments in stem cell therapy in cardiology Ivonne H Schulman & Joshua M Hare* A novel therapeutic strategy to prevent or reverse ventricular remodeling, the substrate for heart failure and arrhythmias following a myocardial infarction, is the use of cell-based therapy. Successful cell-based tissue regeneration involves a complex orchestration of cellular and molecular events that include stem cell engraftment and differentiation, secretion of anti-inflammatory and angiogenic mediators, and proliferation of endogenous cardiac stem cells. Recent therapeutic approaches involve bone marrowderived mononuclear cells and mesenchymal stem cells, adipose tissue-derived stem cells, cardiac-derived stem cells and cell combinations. Clinical trials employing mesenchymal stem cells and cardiac-derived stem cells have demonstrated efficacy in infarct size reduction and regional wall contractility improvement. Regarding delivery methods, the safety of catheter-based, transendocardial stem cell injection has been established. These proof-of-concept studies have paved the way for ongoing pivotal trials. Future studies will focus on determining the most efficacious cell type(s) and/or cell combinations and the mechanisms underlying their therapeutic effects. Keywords: cardiac stem cell n cell transplantation n heart failure n ischemic heart disease n mesenchymal stem cell n myocardial infarction
Ischemic heart disease affects an estimated 16.3 million Americans and is a leading cause of heart failure as well as cardiovascular mortality, accounting for approximately one in six deaths in the USA [1] . Over the past half-century, advances in risk factor modification and pharmacological and interventional therapeutic approaches have dramatically improved the quality and quantity of life of patients with ischemic heart disease. However, existing therapeutic strategies do not directly reverse the scar formation or progressive ventricular remodeling that follows a myocardial infarction (MI), a process that eventually leads to ventricular dysfunction and arrhythmias. Stem cell therapy has emerged as a strategy aimed at preventing or reversing myocardial injury and promoting cardiac tissue regeneration (Figure 1).
Preclinical models of ischemic heart disease employing large animals have been instrumental in advancing phenotypic and mechanistic insights underlying stem cell therapy, as well as the safety and efficacy of various methods of cell delivery and usefulness and precision of diverse imaging modalities to assess therapeutic efficacy [2–4] . Regarding the types of stem cells, embryonic stem cells (ESCs) can differentiate into all adult cell types and have been shown to have the potential for cardiac regeneration in animal models. However, ethical, legal, biological [5] and immunologic [6] issues have hindered their use in human trials. An attractive alternative to ESCs is the programming of adult somatic cells into ESC-like, induced-pluripotent stem cells [7] or induced cardiomyocytes [8] . These approaches have only recently started to be investigated clinically
and the reproducibility, durability and safety of human cell reprogramming and genetic-engineering strategies remain the subject of investigation [9,10] . Nevertheless, the cardiovascular stem cell field has rapidly advanced and now numerous adult stem cell sources, including bone marrow-derived mono nuclear cells (BMMNCs) [2,11–16] , mesenchymal stem cells (MSCs) [2,17] , adipose tissue-derived stem cells [18] and cardiac-derived stem cells [19,20] , are under clinical evaluation. It has become evident that the mechanisms underlying the therapeutic strategy of stem cell transplantation involves an orchestration of events including reduction of cardiac cell death and fibrosis, as well as stimulation of neovascularization and endogenous cell proliferation. With regards to MSCs, existing mechanistic studies support the importance of the release
Ivonne H Schulman, Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA; and Nephrology-Hypertension Section, Miami Veterans Affairs Healthcare System, Miami, FL, USA *Author for correspondence: Joshua M Hare, Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA; Tel.: +1 305 243 1999; Fax: +1 305 243 3906; jhare@med.miami.edu
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of trophic, anti-inflammatory and immunomodulatory factors in addition to cell engraftment, differentiation and, notably, stimulation of endogenous cardiac stem cell (CSC) recruitment and differentiation [21] . This enhanced understanding of phenotypic response and mechanistic appreciation of the underpinnings of stem cell therapy can be harnessed for improved trial design, as well as for development of newer generations and combinations of stem cell products that have greater efficacy and sustainability (durability) [4,22] . The growing human phenotypic data from recent and ongoing clinical trials supports the notion that stem cell therapy is safe and has the capacity for repair of cardiac structure as well as restoration of cardiac function [4,17] . This article reviews the most recent
developments in the clinical use of stem cells as a therapeutic strategy for cardiac structural and functional repair in acute and chronic ischemic heart disease.
Recent developments
Acute MI Several studies over the past decade have tested intracoronary bone marrow infusions in patients with acute MI (Table 1). In the TOPCARE-AMI trial, patients with acute MI received an intracoronary infusion of ex vivo expanded BMMNCs or culture-enriched endothelial progenitor cells derived from peripheral blood MNCs [11] . The 5-year results demonstrated the long-term safety of intracoronary delivery of autologous BMMNCs in acute MI and, notably, the sustainability of the left ventricular
Figure 1. Translational development of novel clinical therapies for heart disease.
Animal Facility Preclinical safety and efficacy studies Therapeutic hypothesis tested
Laboratory Cell discovery Mechanistic hypotheses tested
Clinic Phase I–III safety and efficacy trials Novel mechanistic and therapeutic hypotheses formulated
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(LV) ejection fraction (LVEF) improvement in the treated group [11] . Most recently, a meta-analysis of 50 studies (2626 patients) confirmed the idea that this strategy prevents remodeling by reducing infarct size and LV chamber enlargement and that these benefits persisted during long-term follow-up [23] . Importantly, this meta-analysis confirmed a long-observed clinical benefit that is out of proportion to increases in cardiac function: BMMNC therapy reduced the incidence of death, recurrent MI and stent thrombosis in patients with ischemic heart disease. This evaluation strongly supports the soon-to-start BAMI trial (NCT01569178). This is a multinational, randomized, controlled, Phase III study that will investigate whether intracoronary infusion of autologous BMMNCs is safe and reduces all-cause mortality in patients with reduced LVEF (EF ≤45%) after successful reperfusion for acute MI. Pharmacologic and genetic approaches are also under investigation with the aim of enhancing the therapeutic efficacy of cell-based therapy [9,10] . For instance, the Phase II clinical trial ENACT-AMI will investigate the efficacy and safety of autologous EPCs and autologous EPCs transfected with human endothelial nitric oxide synthase (NCT00936819). Two clinical trials, one ongoing and one completed, are testing the impact of cell therapy timing on therapeutic potential. The ongoing Phase II trial developed by the Cardiovascular Cell Therapy Research Network, the TIME study, is comparing the safety and efficacy of intracoronary delivery of BMMNCs at 3 and 7 days post-MI in patients with ST-segment elevation [16] . On the other hand, the LateTIME trial investigated whether delaying BMMNC delivery for 2–3 weeks following MI and primary percutaneous coronary intervention improves global and regional LV function [13,14] . No significant changes between baseline future science group
Key developments in stem cell therapy in cardiology
and 6-month measures were observed in LVEF and wall motion in the infarct and border zones, as measured by cardiac MRI, in the BMMNC group compared with placebo. These findings indicate that the 2–3-week post-MI time-point may exceed the therapeutic window of intracoronary BMMNC therapy. There is growing evidence that cell dose impacts therapeutic potential. In a randomized, controlled, open-label study, infarct-related artery infusion of CD34 + cells in patients with acute MI (AMR-01; NCT00313339), patients underwent infarct-related artery infusion of autologous bone marrow-derived CD34 + cells after ST elevation MI at a median of 8.3 days after coronary stenting [24] . Three dose levels were investigated in cohorts of five patients each. CD34 + cells are hematopoietic stem
cells that have been shown to improve perfusion and function in myocardial and limb ischemia models by stimulating neovascularization directly through endothelial lineage differentiation and indirectly through the secretion of proangiogenic factors. This small, doseescalation pilot study reported that improved perfusion and infarct size reduction correlated with the quantity and mobility of the infused CD34 + cells. With regard to other cell types and sources, the current evidence supporting the use of MSCs as a cellbased therapeutic for ischemic heart disease include ease of accessibility for isolation, the enormous expansion potential in culture, presumptive plasticity, immunomodulatory prop erties, potential as an allogeneic cell therapeutic, paracrine-mediated effects,
homing and migratory behavior to sites of tissue injury, and ethical considerations. Of particular clinical interest is the potential use of allogeneic MSCs, which would preclude the need for the patients’ bone marrow aspiration and the timely culture expansion of their MSCs. In this regard, bone marrowderived allogeneic MSCs (Prochymal®; Osiris Therapeutics, Inc.) were recently investigated in a Phase II, 220 patient study in the setting of acute MI with depressed EF. It was preliminarily reported by Osiris [Unpublished Data] that a single intravenous infusion of either Prochymal or placebo within 7 days of an acute heart attack significantly reduced cardiac hypertrophy, stressinduced ventricular arrhythmia, heart failure and rehospitalization for cardiac complications compared with patients receiving placebo.
Table 1. Recently published stem cell therapy clinical trials for ischemic heart disease. Trial LateTIME Randomized, controlled, double-blind pilot trial evaluating the safety and effect of intracoronary administration of BMMNCs 2–3 weeks following acute myocardial infarction TOPCARE-AMI 5‑year results First randomized study investigating the effects of intracoronary infusion of circulating or bone marrow-derived progenitor cells in patients with successfully reperfused acute myocardial infarction FOCUS-CCTRN Randomized, double-blind, placebo-controlled study investigating the efficacy of transendocardial delivery of BMMNCs in patients with chronic ischemic cardiomyopathy TAC-HFT (ongoing) Randomized, double-blinded, placebo-controlled trial evaluating the safety and efficacy of percutaneous delivery with a transendocardial catheter delivery system of autologous bone marrow-derived MSCs or BMMNCs in patients with chronic ischemic cardiomyopathy and heart failure secondary to myocardial infarction SCIPIO (ongoing) Randomized, placebo-controlled study investigating the safety of intracoronary cardiac stem cell therapy in patients with chronic ischemic cardiomyopathy CADUCEUS Randomized, placebo-controlled, dose-escalation study of the safety and efficacy of intracoronary delivery of cardiospherederived stem cells in patients with ischemic cardiomyopathy and a recent myocardial infarction
Year reported
Type of trial
Patients (n)
Cell type
Ref.
(2011)
Phase II RCT
87
Autologous BMMNCs
[13]
(2011)
Phase I RCT
55
Autologous BMMNCs
[11]
(2012)
Phase II RCT
92
Autologous BMMNCs
[15]
(2011)
Phase I/II RCT
8
Autologous MSCs BMMNCs
[2]
(2011)
Phase I RCT
23
Autologous c-kit+ cardiac stem cells
[19]
(2012)
Phase I RCT
25
Autologous cardiospherederived stem cells
[20]
BMMNC: Bone marrow-derived mononuclear cell; MSC: Mesenchymal stem cell; RCT: Randomized clinical trial.
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19
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In terms of the source of MSCs, there is also preclinical evidence for the therapeutic potential of adipose tissuederived MSCs [18] , but no clinical trials have been initiated yet in acute MI patients. However, the noncultured adipose stromal vascular fraction, a heterogeneous population of cells with multilineage differentiation potential, is being tested in two clinical trials. The first study, the APOLLO trial (NCT00442806), is a double-blind, placebo-controlled trial evaluating the safety (defined as major adverse cardiac and cerebral events at 6 months) of intracoronary infusion of autologous adipose-derived stem and regenerative cells in acute MI patients after successful revascularization. A lipoaspirate is obtained by liposuction under local anesthesia and the adiposederived stem and regenerative cells are isolated using the Celution™ System (Cytori Therapeutics). The preliminary data, reported at the 7th International Symposium on Stem Cell Therapy and Cardiovascular Innovation, Madrid, Spain, in May 2010, showed improvement in LVEF, reduction in infarct size, and improvement in myocardial perfusion [25] . A Phase II/III trial the ADVANCE study (NCT01216995) has been initiated to further evaluate the efficacy of this approach, defined as reduction in infarct size at 6 months. Chronic ischemic cardiomyopathy & heart failure The FOCUS-CCTRN is a Phase II trial in patients with chronic ischemic cardiomyopathy that investigated the 6-month efficacy of transendocardial delivery of BMMNCs on myocardial function and perfusion [15] . Although the study showed no significant effect on LV end-systolic volume, maximal oxygen consumption or myocardial perfusion, exploratory analyses demonstrated significant improvement in stroke volume and LVEF, which correlated with higher bone marrow CD34 + and CD133 + progenitor cell counts. These findings support the notion that certain 20
bone marrow-derived cell populations may provide a greater regenerative benefit and thereby determine clinical efficacy. In this regard, the ACT34CMI (Adult Autologous CD34 + Stem Cells; NCT00300053) investigators conducted a double-blind, randomized, Phase II clinical trial to evaluate the safety and efficacy of intramyocardial injections of autologous CD34 + cells in patients with refractory chronic myocardial ischemia on maximal therapy who were not suitable candidates for conventional revascularization [26] . Cell therapy was associated with significant improvements in angina frequency and exercise tolerance at both 6 and 12 months compared with placebo treatment, supporting the conduct of larger-scale studies to verify these beneficial effects in patients with refractory angina. Similarly, a smaller randomized, controlled clinical trial in patients with dilated cardiomyopathy reported that intracoronary infusion of CD34 + cells was associated with an increase in LVEF and 6‑min walk distance and a lower secondary end point of 1-year mortality or heart transplantation [27] . Our group has shown in a preclinical large animal model of chronic MI that surgical injection of bone marrowderived autologous as well as allogeneic MSCs results in a reduction in infarct size and an increase in regional myocardial contractility [21,28,29] . These findings are being translated into improvements in clinical outcomes. The results from the first eight patients of the TAC-HFT trial have recently been published [2] . This Phase I/II, randomized, doubleblind, placebo-controlled trial evaluated the safety and efficacy of percutaneous delivery with a transendocardial catheter delivery system of autologous bone marrow-derived MSCs or BMMNCs in patients with chronic ischemic cardiomyopathy and heart failure secondary to MI. The first eight patients (four received MSCs and four received BMMNCs) demonstrated decreased infarct size and improved Regen. Med. (2012) 7(6 Suppl.)
regional contractility. Moreover, it was noted that improvements in regional function observed at 3 months after cell therapy predicted the degree of LV reverse remodeling after 12 months. Importantly, the findings from our preclinical studies as well as this clinical study suggest that the selection of end points, such as infarct size and regional contractility, which can be directly measured and accurately reflect clinical outcomes, could represent more suitable measures of cell therapy efficacy than global LVEF, which most cell therapy trials have used as the primary efficacy end point [2,3] . In addition, our group is conducting two clinical trials comparing the safety and efficacy of bone marrow-derived allogeneic and autologous MSCs. The initial findings of the POSEIDON study (NCT01087996), the first direct randomized head-to-head comparison of autologous versus allogeneic MSCs delivered by transendocardial injection, will be presented as a late-breaking clinical trial at the American Heart Association Scientific Sessions in November 2012 [30] . A parallel, ongoing clinical trial, POSEIDON-DCM (NCT01392625), aims to establish the safety and efficacy of transendocardial autologous versus allogeneic MSC therapy in patients with nonischemic, dilated cardiomyopathy. Currently, there is only one ongoing clinical trial using culture-expanded adipose tissue-derived MSCs, the MyStromalCell trial (NCT01449032). This double-blind, placebo-controlled trial in patients with chronic ischemic heart disease is investigating the efficacy and safety of intramyocardial delivery of VEGF-A165-stimulated autologous adipose tissue-derived MSCs to improve myocardial perfusion and exercise capacity and reduce symptoms. The PRECISE trial (NCT00426868), a randomized, controlled clinical trial using noncultured adipose stromal vascular fraction cells, tested the effect of intramyocardial delivery in patients future science group
Key developments in stem cell therapy in cardiology
with chronic ischemic cardiomyopathy. The preliminary data, reported at the 7th International Symposium on Stem Cell Therapy and Cardiovascular Innovation, showed a reduction in infarct size and an improvement in maximum oxygen consumption and exercise capacity [31] . Another extremely promising cell-based therapeutic for chronic ischemic cardiomyopathy and heart failure are cardiac-derived stem cells. Cardiac-derived stem cells under investigation include cells that express the SCF receptor c-kit (CD117) [32] and multicellular clusters named cardiospheres [33] . Both can be harvested from patient endomyocardial biopsies and expanded ex vivo to generate large numbers of autologous cells that can be delivered back to the patient [33,34] . Recently published results from the ongoing Phase I clinical trial, SCIPIO, demonstrated that intracoronary infusion of autologous c-kit+ CSCs is safe and effective at improving LV systolic function and reducing infarct size in patients with heart failure (LVEF <40%) after MI who had undergone coronary artery bypass grafting [19] . Notably, LVEF significantly increased from 30.3 ± 1.9 to 38.5 ± 2.8% (n = 14) at 4 months after infusion of CSCs, whereas no change in LVEF was evident in the control patients (n = 7). There was evidence of an even greater effect at 1 year, with an increase in LVEF of 12.3 ± 2.1 EF units versus baseline (n = 8). The increase in LVEF was associated with an improvement in regional wall contractility in the infused LV regions as well as all the LV segments combined. Furthermore, infarct size (mean infarct weight assessed with cardiac MRI) decreased by 24% at 4 months and 30% at 1 year (n = 7). These dramatic initial results are highly encouraging and warrant further investigation in larger studies. On the other hand, the recently completed CADUCEUS trial [20] is a Phase I randomized clinical trial of cardiospheres as a cell-based therapeutic. A total of 25 patients with ischemic future science group
heart disease, successful percutaneous coronary revascularization, and LV dysfunction (mean baseline LVEF was 39 ± 12%) were randomized to receive infarct-related coronary artery infusion of cardiosphere-derived cells or standard care 1.5–3 months after MI. A reduction in scar mass (28% by 6 months and 42% by 12 months) and an increase in viable heart mass, regional contractility and regional systolic wall thickening was observed 6 months following cell therapy, as assessed by cardiac MRI. However, in contrast to the study of cultureexpanded c-kit+ CSCs, cardiospheres did not augment parameters of integrated cardiac performance such as LVEF, end-diastolic volume or end-systolic volume. The differences in clinical outcomes may be related to variability in study design, including the target patient population, delivery method, cell dose and CSC-specific characteristics. Nevertheless, the encouraging results from these two clinical trials provide rationale for larger randomized trials that will extend these observations to test whether cardiac-derived stem cell infusion produces sustainable clinical benefits in patients with ischemic heart disease.
Future perspectives Although there has been significant progress in the clinical translation of cell therapy over the past decade, uncertainties remain regarding the most efficacious cell type, source and quantity, as well as route and timing of delivery. Adding to the complexity, there is growing evidence that stem cells harvested from patients do not produce the same benefit as those from healthy individuals [35] . Collectively, these issues highlight the need for further investigation of the mechanisms underlying stem cell survival, plasticity and function. In addition, pharmacologic and genetic strategies are being developed in an effort to improve stem cell survival, homing and engraftment, which will potentially translate into better clinical outcomes www.futuremedicine.com
[9,10,36–39] . Two novel and exciting possibilities are the combination of different stem cells [40] or of cell and gene therapy [9,10,36–39] . In addition, the discovery of microRNAs as regulators of cardiovascular biology and stem cell differentiation have made them attractive targets to optimize cell-based therapies [41] .
One of the major challenges of cellbased therapy is the survival of cells after delivery into the recipient tissue microenvironment. Ischemia creates a hostile microenvironment due to locally expressed proinflammatory and proapoptotic cytokines inducing cell death. Various approaches to inhibit local inflammation and promote cell survival and tissue regeneration are being investigated, including preconditioning by in vitro incubation of stem cells with prosurvival factors, or transfection of stem cells with prosurvival or antiapoptotic genes prior to cell delivery [9,10,36–39] . Combination cell therapy Based on our findings that MSCs interact with endogenous c-kit+ CSCs via connexin-43 gap junctions and stimulate their proliferation and differentiation [21] , we hypothesized that combination therapy may provide greater cardiac structural and functional repair. Recently, this combination of cell types have demonstrated efficacy in eliciting a favorable remodeling response in preclinical models. A preliminary report in a porcine model of MI showed that the combination of MSCs and c-kit+ CSCs is more effective at reducing infarct size and restoring cardiac function than either cell type alone [40] . These findings support the initiation of clinical trials in patients with chronic ischemic cardiomyopathy, which are currently in the planning phase. Novel in vivo differentiation & imaging approaches Recent studies employing animal models of ischemic heart disease 21
Schulman & Hare
have reported the development of novel approaches to enhance in vivo differentiation of endogenous cells into cardiomyocytes [42] . Song et al. demonstrated that a cocktail of four transcription factors (GATA4, HAND2, MEF2C and TBX5)
reprogrammed adult fibroblasts into cardiomyocytes in vitro [42] . Notably, using a retrovirus to deliver the transcription factors to the hearts of mice, they demonstrated that expression of these four transcription factors reprograms nonmyocytes
to cardiomyocytes in vivo and attenuates cardiac dysfunction after MI. Although further studies in large animal models are required before translation into clinical trials, this is an exciting approach with potential for endogenous cardiac regeneration that
Key points Acute myocardial infarction Intracoronary delivery of autologous bone marrow-derived mononuclear cells (BMMNCs) prevents remodeling after acute myocardial infarction (MI) by reducing infarct size and left ventricular chamber enlargement. BMMNC therapy also reduced the incidence of death, recurrent MI and stent thrombosis. A Phase II study employing bone marrow-derived allogeneic mesenchymal stem cells (MSCs; Prochymal®; Osiris Therapeutics, Inc.) in the setting of acute MI recently reported preliminary findings that an intravenous infusion of Prochymal within 7 days of an acute MI significantly reduced cardiac hypertrophy, stress-induced ventricular arrhythmia, heart failure and rehospitalization for cardiac complications. A Phase II/III safety and efficacy study of autologous adipose-derived stem and regenerative cells delivered via the intracoronary route in acute MI patients (ADVANCE Study) has been initiated. Chronic ischemic cardiomyopathy & heart failure The Phase II trial FOCUS-CCTRN investigated the efficacy of transendocardial delivery of BMMNCs in patients with chronic ischemic cardiomyopathy. Exploratory analyses showed an improvement in left ventricular ejection fraction that was associated with higher bone marrow CD34+ and CD133+ progenitor cell counts, suggesting that certain bone marrow cell populations may provide a greater regenerative benefit and determine clinical efficacy. Results from the first eight patients of TAC-HFT, a Phase I/II, randomized, double-blind, placebo-controlled trial, demonstrated the safety and efficacy of percutaneous delivery with a transendocardial catheter delivery system of autologous bone marrow-derived MSCs or BMMNCs in patients with chronic ischemic cardiomyopathy. The patients exhibited improved regional myocardial contractility and decreased infarct size, and the improvements in regional function observed at 3 months after cell therapy predicted the degree of reverse remodeling after 12 months. The POSEIDON study (NCT01087996), the first randomized head-to-head comparison of autologous versus allogeneic MSCs delivered by transendocardial injection, will be presented as a late-breaking clinical trial at the American Heart Association Scientific Sessions in November 2012. The ongoing MyStromalCell Trial is the first randomized, double-blind, controlled study investigating intramyocardial VEGF-A165-stimulated adipose tissue-derived MSCs. Cardiac-derived stem cells The Phase I clinical trial SCIPIO demonstrated that intracoronary infusion of autologous c-kit+ cardiac stem cells is safe and effective at improving left ventricular systolic function and reducing infarct size in patients with chronic ischemic cardiomyopathy. The CADUCEUS trial, a Phase I randomized clinical trial of cardiospheres as a cell-based therapeutic, demonstrated a reduction in scar mass and an increase in viable heart mass, regional contractility and regional systolic wall thickening at 6 months after cell therapy. Combination cell therapy Preclinical studies showed that the combination of MSCs and c-kit+ cardiac stem cells is more effective at reducing infarct size and restoring cardiac function than either cell type alone, supporting the planned initiation of clinical trials in patients with chronic ischemic cardiomyopathy. Novel in vivo differentiation & imaging approaches In preclinical studies, a cocktail of four transcription factors (GATA4, HAND2, MEF2C and TBX5) reprogrammed adult fibroblasts into cardiomyocytes in vitro and in vivo and attenuated cardiac dysfunction after MI. Future studies in large animal models are required to investigate further the safety and efficacy of this novel approach for endogenous cardiac regeneration. In preclinical studies employing a large animal model of MI, sodium iodide symporter transgene imaging was shown to be a feasible approach to follow in vivo survival, engraftment and distribution of human induced pluripotent stem cell derivatives. Conclusion Future studies investigating the use of cell-based therapy in ischemic heart disease will focus on determining the most efficacious and safe cell type(s) and/or cell combinations to use as well as how cell–cell interactions mediate the cardiac regenerative effects.
22
Regen. Med. (2012) 7(6 Suppl.)
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Key developments in stem cell therapy in cardiology
would obviate the need for stem cell transplantation. Nevertheless, there are many additional benefits that cell therapy brings to bear, and the relative value of each approach will require future investigation.
it showed vascular differentiation and long-term engraftment of human induced pluripotent stem cells in a clinically relevant large animal model of MI.
Imaging approaches that allow for long-term monitoring of viable transplanted stem cells are necessary for the evaluation of novel cell-based therapies in preclinical and clinical studies. In a recent study, sodium iodide symporter transgene imaging was evaluated as an approach to follow in vivo survival, engraftment and distribution of human-induced pluripotent stem cell derivatives in a porcine model of MI [43] . This study demonstrated the feasibility of repeated long-term in vivo imaging of viability and tissue distribution of cellular grafts in large animals. In addition,
Conclusion In summary, cell-based therapy for ischemic cardiomyopathy and heart failure has emerged as a highly promising therapeutic approach that will expand the benefits obtained by current pharmacologic and revascularization approaches by directly reversing scar formation and promoting myocardial regeneration. The next stage of development for the clinical use of cell therapy should focus on investigating novel formulations, particularly the best cell type(s) and/or cell combinations to use and elucidation of the mechanisms by
which various stem cells interact with host cells and/or each other and elicit their regenerative effects.
Financial & competing interests disclosure JM Hare is supported by NIH grants: RO1 HL094849, P20 HL101443, RO1 HL084275, RO1 HL107110, RO1 HL110737 and UM1 HL113460. JM Hare is listed on a patent for cardiac cell-based therapy, receives research support from Biocardia, is a Consultant to Kardia, and reports an equity interest in Vestion, Inc. IH Schulman has no conflict of interest that could influence this work. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
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RESEARCH & DEVELOPMENT
Research Update Stem cells and neurodegenerative diseases: where is it all going? Roger A Barker* Over the last few years there have been a number of major breakthroughs in the development of stem cells for diseases of the CNS. One of these has been in the ability to reprogram adult somatic cells to a more pluripotent state as well as directly to neurons and, by so doing, use patient-derived cells to study disease. In addition, the capacity to engineer embryonic stem cells to defined neuronal fates in the absence of proliferative contaminant cells is now feasible, which opens up the possibility of using these cells for cell transplantation. In this review, we will discuss how these developments have come about, particularly in the context of Parkinson’s disease, and what this means for the future of this whole field over the next few years. KEYWORDS: n induced pluripotent stem cells n neural grafting n Parkinson’s disease n stem cells
Chronic neurodegenerative disorders of the CNS, which target the aging brain, are set to increase as the population ages. As such, finding ways to better understand and treat these conditions is a major challenge given the personal and economic costs. These disorders include Alzheimer’s disease (AD), Parkinson’s disease (PD) and a host of other rarer conditions, such as Huntington’s disease (HD), frontotemporal dementia and amyotrophic lateral sclerosis. Each of these disorders is defined by the loss of specific populations of neurons, with a characteristic pathological pattern of protein aggregation – for example, in the case of PD the loss of the nigrostriatal dopaminergic pathway and the presence of alpha synuclein-containing Lewy bodies. While this is a useful starting point by which to define these diseases, it is nevertheless important to realize that these chronic neurodegenerative disorders: Have a much greater extent of pathological burden than was once recognized and as such these diseases
target a whole range of different neuronal populations, rather than just one neuronal network; Have a pathology that is not confined to the neurons but involves glial cells and an inflammatory element; Often display mixed profiles of pathology, typically with a significant vascular disease burden in the brain, particularly in those conditions that affect the more elderly; Are heterogeneous with a complex etiology; May have an effect on endogenous neurogenic processes. Viewing these disorders as a discrete entity with a single pathology and core cell loss has been a useful first approximation, which has to date been best modelled using either targeted lesions (e.g., a lesion to the dopaminergic nigrostriatal neurons in the case of PD) or the generation of a transgenic murine model if the condition had a known Mendelian basis. While these models are useful, they provide only
*Author for correspondence: Roger A Barker, Cambridge Centre for Brain Repair, Department of Clinical Neuroscience, University of Cambridge, Forvie Site, Robinson Way, Cambridge CB2 OPY, UK; Tel.: +44 1223 331 160; Fax: +44 1223 331 174; rab46@cam.ac.uk
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limited information as the majority of patients with the most common neurodegenerative conditions have a non-Mendelian form of the condition with a complex evolving pathological process across networks of cells. However, the newly developed capacity to reprogram adult somatic cells from patients with these diseases has opened up new possibilities in this area. In this short review, the author will discuss how this technology of inducible stem cells has been used to better understand these diseases and how stem cells are being viewed for cell transplantation.
Disease modeling: the use of inducible cells Using stem cells to dissect the cellular events underlying the genesis of different neurodegenerative conditions has gained prominence following the seminal demonstration that differentiated human somatic cells could be reprogrammed into a pluripotent state by the overexpression of a set of defined transcription factors [1,2] . This technology using induced pluripotent stem (iPS) cells means that cells can be grown from patients themselves that have the capacity to proliferate indefinitely in culture and a pluripotency profile that enables them
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Figure 1. Two types of cell reprogramming strategies. Modeling disease with induced pluripotent stem cells or direct neuronal conversion.
Neurons
Induced pluripotent cells
Somatic cells
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to be differentiated into any cell type, including different types of neurons. More recently it has been shown that it is possible to directly reprogram human somatic cells into neurons without having to go through an intermediate pluripotent state [3] . Again these reprogrammed induced neurons could be extremely useful for screening potential compounds for therapeutic purposes, as well as studying disease pathways. So what has been shown with these two types of cell reprogramming strategies (Figure 1), and what has this told us about neurodegenerative disorders? Modeling disease with iPS cells iPS cells derived from patients offer a powerful in vitro model by which to study disease, as these cells carry all of the necessary genetic risk factors for that disorder. The ability to make such cell lines and derive relevant neurons from them has now been achieved in a range of conditions but mainly from patients with Mendelian forms of disease such as some types of PD (see below) and AD, as well as HD and some genetic forms of motorneuron disease and dementia [4–8] . These studies have largely used fibroblasts harvested from skin biopsies and a variety of different reprogramming and culturing regimes – techniques that are constantly being refined and improved upon. These studies have drawn a number of important conclusions about the use of iPS cells to model disease. A key finding is that relevant populations of neurons can be derived using this approach. Importantly though, it is increasingly being recognized that such cells need to be shown to be true neurons of the type relevant for the disease state (e.g., dopaminergic nigral neurons in the case of PD). In other words, the character of the derived neurons needs to be verified using not just immuncytochemistry but transcription profiles, along with evidence of electrical excitability and transmitter release. 28
The neurons derived using this approach often have a subtle pathology, if any. This can be brought out by increasing the time spent in culture and/or the use of stressful stimuli. For example, Soldner and colleagues found no differences between the dopaminergic neurons derived from the iPS cells from PD patients and controls after 30 days in culture even though they showed that the cells had a true ventral midbrain dopaminergic neuronal phenotype [9,10] . However, long-term culturing (<75 days) of these cells did reveal changes, with a decrease in the number and length of neurites, and an increased susceptibility to degeneration and abnormalities in autophagosome function [10] . Another issue in modeling diseases using somatic cells is the variable biological characteristics of the cells, which include differences in genetic background, as well as in the cell derivation and differentiation processes [9,11,12] , along with the genetic alterations introduced during the reprogramming process [13–15] . All of this means that it is unclear whether deficits found in the cells truly relate to the disease state rather than the person or the derivation procedure itself. In cases of diseases caused by a single abnormal gene, this can be controlled for. For example, Soldner and colleagues (2011) generated human iPS cell lines from a patient carrying the A53T (G209) mutation in the SNCA gene, which they then corrected using zinc finger nuclease-mediated genome editing [16] . By so doing, they generated iPS cells that differ only in this gene (i.e., a gene that gives the cell its susceptibility for PD), providing genetically matched control cells to study the effects of that specific mutation. However, while this approach is appealing to study cellular mechanisms associated with Mendelian forms of disease, it excludes the use of iPS cell lines to investigate disorders with a more complex and mixed etiology, such as most cases of AD and PD. Regen. Med. (2012) 7(6 Suppl.)
A further issue is whether iPS cells can truly be used to study pathologies found mainly in the aged CNS, such as in PD or AD? The induction of pluripotency is accompanied by a progressive elongation of telomeres with passaging [17–19] , thus rejuvenating the cells in a similar way to that seen in the embryonic stem (ES) cell state, even in cells derived from aged individuals. However, the telomere chromatin does return to a more mature state when differentiated and iPS cells also retain the DNA methylation patterns of their original state before derivation [20–22] , all of which argues for them still being relevant as an in vitro model for these disorders. Finally, most diseases of the CNS are now known to have multiple players, such that disease pathogenesis involves not just neurons but glia, as well as inflammatory cells. The ability to model disease using the conversion of somatic cells from patients would therefore benefit from the development of cocultures of multiple induced cell lineages. In this respect, the ability to make these different cell types and even induced neural stem cells from fibroblasts would be useful [23–26] . In terms of the inflammatory components and the microglia, such cells have been generated from mouse ES cells [27] , but the successful reprogramming of somatic cells, such as fibroblasts, into this cell type has yet to be reported. Modeling disease with direct neuronal conversion While the use of iPS cells has shown great promise as a way to study disease in vitro, concerns with respect to their utility to do this have arisen (see above) in part because they are reprogrammed back to a more pluripotent stage. To overcome this issue, several groups have developed methods that allow direct conversion of human differentiated somatic cells, such as fibroblasts, into functional neurons, avoiding a pluripotent state [3] . The first proof-of-concept study converted mouse embryonic and future science group
Stem cells & neurodegenerative diseases: where is it all going?
postnatal fibroblasts into functional induced neurons by the overexpression of three transcription factors (Ascl1, Brn2 and Mytl1). These induced neurons displayed appropriate neuronal properties such as the generation of action potentials as well as synapse formation [3] . Human fibroblasts have also now been successfully converted into functional neurons by again overexpressing the same transcription factors [28] , and several subsequent studies have been undertaken to better optimize this approach [29,30] . To date, however, its use in patients is limited in so much as this approach has only been done in AD patients with the generation of functional glutamatergic forebrain neurons from fibroblasts [31] . As the direct conversion does not go through a proliferative state, the quantity of neurons that can be obtained is limited by the number of fibroblasts used as the starting material for conversion and thus, to some, these cells are a less attractive tool by which to study disease. Stem cell transplants Although a number of diseases have been thought suitable for this approach (e.g., HD [32]), the one condition where this has been most explored is PD [33] . While a number of different cell types have been tried to restore the dopaminergic deficits that lie at the heart of PD, the most successful approach to date involves the transplantation of fetal ventral mesencephalic (VM) tissue into the striatum of patients, although the results from this approach have been somewhat inconsistent [34–36] . These studies, which at most have involved a few hundred patients, have shown that VM dopaminergic neurons can survive long term in the PD brain and produce significant functional benefits in some patients [33,36] , implying that nigral dopaminergic neurons derived from stem cells sources should, theoretically, have the same capabilities. The differentiation of human ES cells into dopaminergic neurons using standard future science group
protocols has long been known to be inefficient, but by using combinations of factors known to be involved in normal dopaminergic neuronal development, the yield of dopaminergic cells from such sources can be dramatically improved [37,38] . This ability to make large numbers of functional nigral dopaminergic cells from ES cell sources without teratoma formation has been shown in a number of in vivo transplant studies, although the results until recently were less impressive than older studies using fetal VM tissue [39] . However, a very recent and novel approach from the laboratory of Lorenz Studer has shown that dopaminergic neurons derived from a human ES cell source can have robust effects across a range of animal models of PD [40] , which has raised the very real possibility that dopaminergic neurons derived from an ES cell source may be ready for early clinical trials in patients with PD in the next 5 years.
to show that it is possible to make functional dopaminergic neurons from iPS (and to a lesser extent induced neurons) cells, a number of questions remain to be answered before they can be considered for use in any clinical transplant trial: QQ Do these cells really form mature nigral dopaminergic neurons with the necessary axonal outgrowth and arbor ization required of them to innervate the whole striatum when grafted?
Although the use of ES cells is very promising, there are still concerns with their use, including ethical, immunological and practical issues with their derivation, and as a result iPS and induced neuron cells have been considered as alternatives for grafting. This approach has been assessed in a number of studies, and it has been shown that while it is possible to make functionally relevant nigral dopaminergic neurons from such sources, there are still issues of cellular proliferation within the graft, as well as limited fiber outgrowth and incomplete functional recovery after grafting [41] . In addition, these cells may not be as immunogenically silent as once thought [42] .
QQ Can these cells be reprogrammed to replace all of the cell losses seen in this disease?
More recently, directly converted induced dopaminergic neurons from mouse fibroblasts have been transplanted into 6-OHDA-lesioned rodents [43,44] , with some success, although again their ability to do this seems less than that seen with fetal VM tissue. Therefore, although several proof-ofconcept studies have been undertaken www.futuremedicine.com
QQ How safe are these cells in terms of cell proliferation, dedifferentiation, cell migration and the immune reaction they induce? QQ Do these cells retain a disease-specific vulnerability that will adversely affect their long-term survival and efficacy? QQ In the case of Mendelian forms of disease (including PD), can we repair disease-related mutations in vitro and transplant these cells successfully?
Conclusion The ability to use stem cells to study neurodegenerative diseases has received much attention of late, but it is still not clear whether these cells can truly recapitulate the pathogenic processes in these disorders. It may be that they are ultimately better for doing this in neurodevelopmental disorders of the CNS [45–47] . Nevertheless, the ability to manipulate adult somatic cells from patients with neurodegenerative disorders of the aging CNS to neuronal phenotypes of relevance is now possible, and this may open up exciting new opportunities for cell grafting – although such a therapy would have to be shown to be competitive with the other treatments that are out there, and this includes the cost. However, more realistically it is in the realm of disease modeling and drug screening that they offer most hope, especially given the distributed neuronal pathology seen in all neurodegenerative disorders of the CNS. 29
Barker
Financial & competing interests disclosure The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materia ls d iscussed
in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Key points Parkinson’s disease (PD) is a disorder that has widespread pathology and clinical features with a core loss of the nigral dopaminergic projection neurons. Many Mendelian forms of PD have now been described, and most of these have now been the subject of induced pluripotent stem cell studies. These studies have revealed subtle abnormalities, if any, in the dopaminergic neurons derived from such induced pluripotent stem cells, but they are increasingly being used to study disease pathogenesis and for drug screening. It is now possible to make nigral dopaminergic neurons directly from skin fibroblasts, although their capacity to repair the brain after grafting is not known. Embryonic stem cell-derived dopaminergic neurons can be generated that have long-term functional benefits in animal models of PD without problems of tumor formation or cellular overgrowth. The ability to translate these new stem cell-based therapies into early trials in patients with PD is still some way off, but lessons learnt from the clinical fetal ventral mesencephalic studies may be instructive in this process.
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RESEARCH & DEVELOPMENT
Research Update Ophthalmologic stem cell transplantation therapies Timothy A Blenkinsop‡, Barbara Corneo‡, Sally Temple & Jeffrey H Stern* Vision loss is a major social issue, with more than 20 million people over the age of 18 years affected in the USA alone. Loss of vision is feared more than premature death or cardiovascular disease, according to a recent Society for Consumer Research group survey. The annual direct cost of medical care for the most prevalent eye disease, age-related macular degeneration, was estimated at US$255 billion in 2010 with an additional economic impact of US$88 billion due to lost productivity and the burden of family and community care for visual disability. With the blossoming of human stem cell research, regenerative treatments are now being developed that can help reduce this burden. Positive results from animal studies demonstrate that stem cell-based transplants can preserve and potentially improve vision. This has led to new clinical trials for several eye diseases that are yielding encouraging results. In the next few years, additional trials and longer-term results are anticipated to further develop ocular regenerative therapies, with the potential to revolutionize our approach to ophthalmic disease and damage. Keywords: bone marrow stem cell n eye disease n human embryonic stem cell n human neural stem cell n induced pluripotent stem cell n limbal stem cell n retinal pigment epithelial stem cell n umbilical cord stem cell
Due to the burden of eye disease, and its relative accessibility, the eye is a prime target for stem cell transplantation therapies, with good surgical access and the ability to visually monitor changes after transplantation being significant advantages [1] . Systemic complications from intraocular agents are rare, and the risks of overgrowth and tumor formation associated with intraocular stem cell transplantation [2–5] are mitigated by the ability of using laser ablation and in extreme cases, evisceration or enucleation [6] . In addition, advanced methods exist to assess the clinical meaningfulness of eye tissue transplant outcome. Quantifiable visualization of the retina with resolution up to a few microns is routine using computerized fundus imaging, laser scanning ophthalmoscopy and optical coherence
tomography technologies. Furthermore, visual function can be assessed rapidly, quantitatively and accurately by visual acuity and visual field measurements. The key sites currently targeted for stem cell transplantation include the cornea, the clear tissue covering the front of the eye that helps focus incoming light, the neural retina, which contains the photoreceptor cells that transduce light into neural electrical signals sent to the visual cortex, and the retinal pigment epithelium (RPE), a single layer of pigmented cells that plays a key role in maintaining the photoreceptor cells and the blood– retina barrier (Figure 1). The neural retina and RPE are CNS tissues, so studies of their replacement with stem cell products serve as a model for stem
cell approaches to less accessible areas of the CNS. In this article we survey recent advances in stem cell-based therapies for ocular disease.
Stem cell types for eye disease clinical trials Human stem cells from a wide variety of sources are being explored for eye disease transplantation therapies (summarized in Figure 2). Some of the transplants are aimed to directly replace lost or damaged tissue, while others replace essential functions of a tissue and/or produce beneficial growth and trophic factors to slow the disease progress. Pluripotent stem cells Pluripotent stem cells are, by definition, able to generate all somatic tissues,
Timothy A Blenkinsop, Neural Stem Cell Institute, Regenerative Research Foundation, One Discovery Drive, Rensselaer, NY12144, USA Barbara Corneo, Neural Stem Cell Institute, Regenerative Research Foundation, One Discovery Drive, Rensselaer, NY12144, USA Sally Temple, Neural Stem Cell Institute, Regenerative Research Foundation, One Discovery Drive, Rensselaer, NY12144, USA *Author for correspondence: Jeffrey H Stern, Neural Stem Cell Institute, Regenerative Research Foundation, One Discovery Drive, Rensselaer, NY12144, USA; Tel.: +1 518 694 8188; Fax: +1 518 694 8187; jeffstern@nynsci.org These authors contributed equally to this work.
‡
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including every cell type found in the eye. Pluripotent human embryonic stem cells (hESCs) or the recently developed induced pluripotent stem cells (iPSCs), bring new hope for eyereplacement therapies by producing ocular cells in essentially unlimited amounts. Moreover, iPSCs made from a patient’s own cells could reduce the need for immunoprotective regimens posttransplantation. An important concern in using pluripotent stem cells is unwanted cell overgrowth or tumor formation. This concern is particularly acute for iPSCs, which are produced from a donor somatic cell type by incorporating key genes that create a primitive, pluripotent state [7] . iPSCs readily form tumors when produced using oncogenic, permanently integrating gene-delivery vectors [8,9] . The use of newly developed techniques now enables elimination of exogenous reprogramming factors [10] , which is anticipated to reduce tumor threat. In addition, efforts are being made to detect and eliminate residual pluripotent cells contaminating the desired differentiated cell product. Neural stem cells Human neural stem cells (NSCs) are typically derived from donated human fetal forebrain tissue. These cells are capable of producing neurons and glia, but have not yet been shown to generate neural retina or retinal pigment epithelium. However, NSCs are capable of producing cells that can substitute several key functions of these tissues and produce specialized trophic factors that could be beneficial [11] . RPE stem cells The recently discovered stem cell in the adult human RPE layer [12] allows the generation of large numbers of RPE cells in tissue culture, and is being explored for production of other ocular cell types. Limbal stem cells One of the earliest stem cells in ocular clinical trials, limbal stem cells produce corneal epithelial cells, which are essential for maintaining the cornea [13] . future science group
Umbilical cord stem cells Umbilical cord tissue is a source of valuable stem cells in the blood and mesenchymal lineages [14] . Although umbilical cord stem cells (UCSCs) do not produce ocular tissues such as neural retina or RPE, UCSCs could slow degeneration through trophic factor release. Banking umbilical cord tissue enables patient-matching. Bone marrow stem cells These have a similar potential to UCSCs, but can be obtained from the adult patient, allowing both allogenic and autologous transplantation [14] .
RPE & photoreceptor diseases. Several blinding diseases, including agerelated macular degeneration (AMD), types of retinitis pigmentosa (RP), Stargardt’s disease and gyrate atrophy (GA), are characterized by dysfunction of the RPE [15] , a monolayer of pigmented, polarized, cobblestone epithelium that lies beneath the neural retina, providing essential support [16–19] . Loss or disease can impair essential RPE functions such as the diurnal phagocytosis and replenishment of photoreceptor outer segments, and thus secondarily produce retinal dysfunction. The most common RPE disease, AMD, affects approximately 10 million Americans over the age of 50 years and is the leading cause of blindness in the elderly [20] . Proof of principle for RPE replacement has been shown by pioneering surgical experiments [21–24] . Autologous surgery is challenging; alternatives using RPE from other donors is limited by the amount of tissue available, a need that stem cells can fulfill. Pluripotent stem cells for retinal & RPE degeneration RPE arises spontaneously from pluripotent human stem cells, albeit slowly and at low efficiency [25–27] . Supplementing with growth factors that stimulate anterior neural plate fate and RPE specification during normal www.futuremedicine.com
development [28–30] or small molecules with similar function [31] improves the speed and efficiency of RPE production. RPE derived from pluripotent stem cells using a variety of methods can preserve vision after transplantation into animal models of retinal degeneration [32] . These breakthrough discoveries have led to clinical trials to determine if such visual preservation can occur in humans. In 2011, the US FDA allowed a Phase I/II open-label, multicenter, nonrandomized, prospective study proposed by Advanced Cell Technology, Inc. (ACT) to determine the safety and potential efficacy of subretinal injection of RPE cells, spontaneously produced from hESCs, in patients with late-stage ‘dry’ AMD (the form of AMD without neovascularization; NCT01344993), or Stargard’s disease (NCT01345006 and NCT01469832). Stargardt’s disease is the most common earlyonset macular degeneration, a genetic disease in which proteins involved in the visual phototransduction cycle are dysfunctional, causing accumulation of waste materials leading to RPE cell death, hence the rationale for RPE replacement. hESC-RPE were generated by ACT collaborators according to good manufacturing practice (GMP) and their purity was determined by qPCR and immunostaining for RPE-specific markers [33] . Lack of pluripotency markers and lack of teratoma formation were used to show negligible contaminant residual hESCs. Phagocytosis of labeled beads was used to demonstrate functionality of the GMP-compliant hESC-RPE cells. This clinical trial enrolling 12 dry AMD and 12 Stargardt’s disease patients to receive uniocular subretinal injection of GMP-compliant hESC-RPE cells, has enrolled the first three patients, receiving a dose of 50,000 cells. Later groups will receive doses up to 200,000 cells. At 4 months after treatment of the first two patients (one with dry AMD, one with Stargardt’s), an early report showed no 33
Blenkinsop, Corneo, Temple & Stern
groups are working to create a suitable matrix that maintains a stable RPE monolayer patch for transplantation. Preclinical studies in pigs using a hESCderived RPE polarized monolayer growing on a coated, nonbiodegradable polyester insert have been completed by a team led by Peter Coffey at the Institute of Ophthalmology in London, UK and UC Santa Barbara, and collaborators at the London Project to Cure Blindness, in partnership with Pfizer [36,37] , and a clinical trial is anticipated.
Eye
Cornea RPE layer
Light
Corneal epithelium Photoreceptors Neural retina
Figure 1. Several tissues in the eye are being targeted for stem cell replacement. RPE: Retinal pigment epithelium.
abnormal growths, teratoma, rejection or inflammation [34]. The AMD patient did not follow the immunosuppression regimen to completion, and no donor cells were detected, potentially indicating that immunosuppression is needed for donor cell survival. Nevertheless, this patient showed visual improvement, from reading 21 letters of the Early Treatment of Diabetic Retinopathy Study eyechart before treatment, to reading 28 letters 3 months after transplantation. Surprisingly, mild improvement was seen also in the untreated eye. For the Stargardt’s disease patient, visual improvement was observed (five letters of the Early Treatment of Diabetic Retinopathy Study chart), including improved color vision and contrast/dark adaptation. ACT has recently enrolled additional patients in the USA and Europe 34
[101] .
It remains to be determined if visual gains observed are due to implanted cells or to a placebo effect, and whether immunosuppression is essential for transplant survival; while the retina has immune privilege [35] , this is often compromised in a diseased eye, especially when the RPE, essential for the blood–retina barrier, is damaged. Nevertheless, the preliminary results are promising and this pioneering hESC clinical trial will be widely watched. Coming soon: transplanting a patch of hESC-derived RPE monolayer Given that the RPE is organized in vivo as a tight, polarized monolayer, it is possible that a transplant of pre-polarized RPE cells will integrate and function better than a cell suspension. Several Regen. Med. (2012) 7(6 Suppl.)
Patient-derived RPE Transplantation of patient-matched RPE cells reduces the necessity of immunosuppression. This could be accomplished using iPSCs generated from patients. At the 2012 International Stem Cell Research meeting in Yokohama, Japan, Masayo Takahashi of the Laboratory for Retinal Regeneration at the Riken Center in Kobe announced a clinical trial for early 2013 enrolling five AMD patients, using GMPcompliant iPSC-derived RPE cells [28,29,38] ; this is the first announced clinical trial using cells derived from iPSCs. At the same meeting, Peter Coffey also reported production of GMP-compliant, iPSC-derived RPE. Another approach toward immunematching being developed in our laboratories at the Neural Stem Cell Institute utilizes the adult human RPE stem cell that can be derived from living patients for autologous transplantation of this tissue-specific stem cell. NSCs for AMD In preclinical studies by StemCells Inc. and collaborators, NSCs isolated from second trimester brain tissue were selected and grown into a defined cell line (HuCNS-SCs). These cells were transplanted into the subretinal space of the Royal College of Surgeons rat, which has an RPE defect that prevents normal phagocytosis of the photoreceptor outer segments, and is a widely used model of retinal degeneration. The implanted NSCs significantly improved photoreceptor survival and vision [39] . Interestingly, future science group
Ophthalmologic stem cell transplantation therapies
Bone marrow
Fetal CNS
Cornea Limbus
hESC-RPE
iPSC-RPE Oral mucosa
Subretinal space
Vitreous
Figure 2. Human stem cell sources explored for eye tissue replacement. hESC: Human embryonic stem cell; iPSC: Induced pluripotent stem cell; Umbilical cord RPE: Retinal pigment epithelium.
these cells did not differentiate into RPE or other retinal cell types, but were still beneficial, potentially by substituting for RPE functions, such as phagocytosis and/or by producing trophic factors that slowed the photoreceptor degeneration. In June 2012, StemCells Inc. announced the initiation of a Phase I/II safety and preliminary efficacy trial. UCSCs for RP & AMD UCSCs transplanted into the subretinal space of the Royal College of Surgeons rat were found to slow vision loss [40] . Based on these data, in 2007, Centocor Biotech (currently Janssen Biotech, Inc., a subsidiary of Johnson & Johnson) began a Phase I clinical trial using their future science group
patented UCSC line, CNTO 2476, to evaluate safety and efficacy outcomes in patients with RP (NCT00458575). In 2010, the study was terminated citing an ‘internal business decision’. In 2010, Janssen Biotech, Inc. began a Phase I/II clinical trial (NCT01226628) transplanting CNTO 2476 into the subretinal space of patients with AMD, administered using a microcatheter, to determine whether UCSCs are safe and can slow degeneration and preserve vision in this disease. Bone marrow stem cells for photoreceptor diseases Bone marrow-derived stem cells have been shown to rescue retinal www.futuremedicine.com
degeneration in mouse models [41,42] . Based on this promising work, clinical trials were started to determine the safety and efficacy of these cells in patients with eye disease. One was conducted to evaluate the short-term (10 months) safety of a single transplantation of 10 × 106 bone marrow-derived mononuclear stem cells in three patients with RP and two patients with cone–rod dystrophy, an early-onset genetic disease involving degeneration of both cones and rods [43,44] . No detectable structural or functional toxicity was found, and further studies are ongoing: in RP patients in Brazil (NCT01560715) and Thailand (NCT01531348); and in Brazil in both 35
Blenkinsop, Corneo, Temple & Stern
AMD (NCT01518127) and ischemic retinopathy (NCT01518842) patients.
Corneal repair The corneal epithelium is essential for maintaining a clear ocular surface. Corneal damage, for example due to alkali burns, can destroy the corneal epithelium, resulting in opacification and blindness [13] . The limbus, a ring of tissue at the edge of the cornea, contains stem cells that divide and differentiate into the corneal epithelium over the lifetime of an individual. In a remarkable series of studies, it was shown that limbal stem cells could be harvested from a healthy area of the limbus in an individual with a damaged cornea and expanded in vitro to form a stratified epithelium that stained positive for a corneal-specific marker. Once mounted on a soft contact lens, these cells can be transplanted to regenerate the patient’s cornea [45,46] , leading in most cases to vision restoration. In a much-anticipated recent report, Graziella Pellegrini and Michele De Luca in Modena, Italy, presented the results of a 10-year follow-up of patients who underwent such autologous limbal stem cell transplantation procedures [47] . They showed that permanent restoration of a transparent, renewing corneal epithelium was observed in 76.6% of eyes and was stable at 10 years [47] . This remarkable, life-altering result demonstrates the enormous potential of autologous stem cell therapy. For patients in which the limbus is completely destroyed, allogeneic transplantation using limbal tissue from an allogenic donor is a suitable, although less successful, alternative [48] . Currently, there are a number of clinical trials ongoing for corneal transplantation of limbal stem cells from both autologous (NCT00845117, NCT 01619189 and NCT01123044) and allogeneic sources (NCT00736307, NCT01619189, NCT01237600 and NCT01562002), transplanted alone (NCT00845117 and NCT01237600), or on amniotic membranes (NCT00736307, NCT01619189, NCT01123044 and 36
NCT01562002). Other stem cell types being tested for this application include cultured oral mucosal epithelial stem cells (NCT01489501 and NCT00491959) and bone marrow-derived mesenchymal stem cells (NCT01562002).
Future perspective
Increasing the ocular target cell repertoire Vision improvement after transplantation of photoreceptors in animal models [49–52] , has spurred efforts to produce human photoreceptors from hESCs and iPSCs in sufficient purity and quantity for transplantation [52–55] . Protocols for the generation of other neural retinal cell types, such as ganglion cells, are also being developed to replace those lost in glaucoma and other optic nerve disorders. In addition to CNS tissue, non-neural ocular elements, such as trabecular tissue that regulates fluid homeostasis, are target tissues for modeling in stem cell cultures and could be used to aid eye repair and slow or prevent disease. Multilayered transplants The normal 3D configuration of eye tissues should be recapitulated to ensure the best possible outcome. In a notable series of experiments, Yoshika Sasai’s group has shown that mouse and human pluripotent stem cells can generate differentiated, 3D structures similar to the embryonic eye cup, containing RPE and neural retina with the appropriate layering and orientation [56,57] . It will be exciting to see how such multicellular growths might provide a more sophisticated 3D transplant, incorporating multiple retinal layers, which could be especially important for patients who have lost both RPE and photoreceptor cells or who have otherwise suffered extensive loss of neural retina. Bioengineered eye tissues In order to build ocular structures, such as the trabecular meshwork or the RPE monolayer, bioengineers are incorporating biocompatible materials with stem cell products [58] . For example, Regen. Med. (2012) 7(6 Suppl.)
Bruch’s membrane, the thick matrix that underlies the RPE, is damaged in AMD, leading to defective exchange of nutrients and cell products with the underlying choroidal vasculature [59] . In approximately 10% of patients with AMD, Bruch’s membrane is compromised such that the choroidal vasculature invades into the retina, causing extensive loss of central vision; so-called ‘wet’ AMD. To help repair the tissue and prevent disease progression, RPE cells can be delivered on a bioengineered Bruch’s membrane capable of preserving and restoring the relationship between the RPE and the choriocapillaris. Several laboratories are working toward the establishment of such matrix materials with different properties of chemical composition, thickness, porosity, topography and biodegradation [60–62] . Disease modeling: GA iPSCs can be generated from patients with eye diseases to study disease etiology and produce ‘disease in a dish’ models valuable for drug screening. For example, GA is a rare, blinding genetic disease caused by dysfunction of a vitamin B6-dependent enzyme that results in deterioration of retina, choroid and RPE [63] . Administration of vitamin B6 is reported to benefit a number of patients. Recently, iPSCs were derived in David Gamm’s laboratory from GA donor dermal fibroblasts and differentiated into RPE. Treatment of the iPSC-derived RPE with vitamin B6 helped determine the dose needed to restore enzymatic activity, aiding treatment of the donor [64] . Such iPSC models will be enormously valuable assets in the fight against eye diseases.
Conclusion Most ocular stem cell translational studies are at early stages – basic research, preclinical and Phase I/II trials – with successful longer term results from autologous limbal cell transplant serving as a beacon for what we might achieve with stem cell approaches. Preserving and restoring vision are key future science group
Ophthalmologic stem cell transplantation therapies
outcomes to be gained, balanced with necessary caution surrounding the risks associated with transplanting living cells with the potential to divide and undergo metaplastic changes. Progress will be swifter as these first trials yield data, allowing the development of more sophisticated therapies that are envisioned
to combine stem cells, bioengineered products and small molecules for a new generation of regenerative therapies.
Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or
entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Key points Eye disease is highly prevalent worldwide, with multiple eye tissues affected. The eye is a prime location for transplantation therapies, with easy surgical access and post-transplantation monitoring, as well as sensitive visual tests for measuring outcomes and a localized safety profile. Stem cell-based transplantation to replace the function of lost cells is a promising therapy for patients with eye diseases. Encouraging results from animal studies demonstrate stem cell-based therapies can preserve and restore vision. A variety of stem cells hold promise for different ocular applications, with some in clinical trials. Human embryonic stem cell-derived retinal pigment epithelium replacement is pioneering the use of human pluripotent stem cells for stem cell-based CNS repair. The future of stem cell therapy includes the use of human stem cells as disease models, enabling a new pathway for drug discovery.
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Website 101 Advanced Cell Technology
www.advancedcell.com
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Scientific Director Dr. Camillo Ricordi (front) and Director of Stem Cell Development for Translational Research Dr. Juan Dominguez-Bendala are working to turn stem cells into insulin-producing cells.
Learn more at DiabetesResearch.org This yearâ&#x20AC;&#x2122;s World Stem Cell Summit aims to â&#x20AC;&#x153;connect, collaborate, cure.â&#x20AC;? At the Diabetes Research Institute (DRI), we are dedicated to that same ideal and proud to serve as a co-organizer of the event. Focusing on translational research, the DRI is committed to conducting relevant research that moves the most promising findings in the lab to patient application in the fastest and most efficient way possible. Its multidisciplinary teams include researchers, engineers and clinicians, as well as a host of international partners, all working together to cure those now living with diabetes. Through this collaborative, fast-track and cure-focused approach, the DRI is able to advance the newest biomedical technologies that have real potential to deliver a cure for diabetes.
RESEARCH & DEVELOPMENT
Research Update From cellular therapies to tissue reprogramming and regenerative strategies in the treatment of diabetes Camillo Ricordi*, Luca Inverardi & Juan Domínguez-Bendala Diabetes mellitus represents a global epidemic affecting over 350 million patients worldwide and projected by the WHO to surpass the 500 million patient mark within the next two decades. Besides Type 1 and Type 2 diabetes mellitus, the study of the endocrine compartment of the pancreas is of great translational interest, as strategies aimed at restoring its mass could become therapies for glycemic dysregulation, drug-related diabetes following diabetogenic therapies, or hyperglycemic disturbances following the treatment of cancer and nesidioblastosis. Such strategies generally fall under one of the ‘three Rs’: replacement (islet transplantation and stem cell differentiation); reprogramming (e.g., from the exocrine compartment of the pancreas); and regeneration (replication and induction of endogenous stem cells). As the latter has been extensively reviewed in recent months by us and others, this article focuses on emerging reprogramming and replacement approaches. Keywords: b-cell regeneration n b-cell replacement n b-cell reprogramming n diabetes n embryonic stem cell n induced pluripotent stem cell n islet transplantation n mesenchymal stem cell
The most frequent form of diabetes mellitus (DM) is the Type 2 variant (T2DM), which prevalently affects subjects in the adult and older age segments. However, we are witnessing an alarming increase in the number of children afflicted by this condition, which parallels the obesity epidemic. T2DM is characterized by insulin resistance, hyperglycemia and eventually dysfunction of the insulin-producing cells. This form of diabetes could be prevented in a significant portion of patients by lifestyle and diet preventive strategies. However, over the years, insufficient insulin production occurs in the majority of patients affected by T2DM. The most severe forms of DM are generally linked to the Type 1 variant (T1DM), which can affect any age group but typically affects children and younger age segments, with a peak
of incidence around 12–13 years of age. In these cases, total or near-total destruction of insulin-producing cells (the b-cells contained in the pancreatic islets – Islets of Langerhans) occurs. Objectives of cellular therapies and regenerative medicine strategies for the treatment of DM are to reverse the disease condition and prevent the development of the severe chronic complications that over time can affect most organ systems in a large proportion of patients. In T1DM, the additional challenge of the underlying autoimmune condition means we must consider strategies that would restore self-tolerance or eliminate the effects of autoimmunity, so that the immune system can no longer destroy the new insulin-producing cells introduced either by regenerating, reprogramming
or replacement (e.g., transplantation of pancreatic islets or stem cell-derived insulin-producing cells). Abrogation of autoimmunity or its effects could be achieved by either tolerance induction strategies or immune protection (e.g., engineered microenvironment or selectively permeable physical barriers like those introduced by conformal, micro- or nano-encapsulation). For a successful therapy, replacement of the insulin-producing cells, reprogramming or regeneration from native precursors must occur in the absence of the lifelong immunosuppression that currently limits the indications of islet transplantation to the most severe cases of T1DM. For expansion of the indications for cellular therapies and regenerative strategies in diabetes, it is critically important to avoid any approach that is likely to increase
Luca Inverardi, University of Miami Cell Transplant Center and Diabetes Research Institute, Miami, FL, USA Juan Domínguez-Bendala, University of Miami Cell Transplant Center and Diabetes Research Institute, Miami, FL, USA *Author for correspondence: Camillo Ricordi, University of Miami Cell Transplant Center and Diabetes Research Institute, Miami, FL, USA; ricordi@miami.edu
10.2217/RME.12.70 © 2012 Future Medicine Ltd
Regen. Med. (2012) 7(6 Suppl.), 41–48
ISSN 1746-0751
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morbidity and mortality rates beyond those already associated with the natural history of disease progression.
State of the art in cell-based therapy for diabetes The history of islet transplantation, which remains the foremost cell therapy for T1DM, has followed each one of the stages of the ‘Gartner hype cycle’, which almost invariably describes the evolution of innovations in all fields of knowledge [1] . The invention of the semiautomated method for islet isolation [2] was arguably the ‘technology trigger’ that made it feasible to consistently reproduce the often difficult and highly specialized process of separating the insulin-producing cells from the rest of the pancreas. This trigger was followed by a ‘peak of inflated expectations’, when the description of a steroidfree immunosuppressive regime (the Edmonton protocol) seemingly solved the problem of long-term graft survival [3] . Unfortunately, it turned out that 5 years after the intervention, only 20% of the islet recipients were still insulin free [4] . Expectations dropped precipitously through the next phase of the hype cycle, aptly named the ‘trough of disillusionment’. Funding for these programs dwindled significantly, and only a few centers kept pushing in the middle of a climate decidedly hostile for the concept of islet transplantation as a viable path to cure diabetes. A slow ‘slope of enlightenment’, however, eventually led to the current ‘plateau of productivity’, which has finally settled the trend somewhere between the initial expectations and the ensuing disillusionment. Novel T-cell-depleting strategies and other immunological interventions are now sufficient to maintain graft survival and function in a manner that stands comparison to the standard of wholepancreas transplantation [5] . As the correction of our expectations has also been accompanied by the emergence of stem cell therapies, efforts at improving islet transplantation are now being 42
re-examined under a more favorable light, which is as an invaluable testing ground for the next generation of cell therapeutics. In other words, the learning curve is expected to be short by the time we are able to safely differentiate stem cells into insulin-producing cells, thus seamlessly expanding the applicability of islet transplantation beyond its current reach. However, there is still controversy regarding the candidate cell type(s) and approach that will ultimately take current therapies to the next level. Since the subject has been recently reviewed in depth [6–14] with a special emphasis on regeneration (the ‘third R’) [15] , this study will focus on a few of the most recent trends in replacement and reprogramming that are shaping this rapidly evolving field.
Embryonic stem & induced pluripotent stem cells The controversy that surrounds the use of embryonic stem (ES) cells for therapy is not a scientific one. There is a broad consensus that they are uniquely qualified to provide the large amounts of tissue required for therapeutic scaleup. To this unparalleled replicative potential, they add the ability to turn into virtually every single tissue of medical interest. If detractors of ES cells had found one such similar cell type from an adult source, there is little doubt that they would have unconditionally embraced it. The oftencited argument that ES cells must be inferior to adult stem cells just because they are not as abundantly represented in clinical trials is obviously misleading, as it ignores the fact that adult stem cells have been in use for more than half a century, whereas human ES cells have been around for only 14 years [16] ; many of them dedicated to overcoming the regulatory issues inherent to the translation of any new therapy. Insulin-producing cells of ES cell origin are arguably closer in nature Regen. Med. (2012) 7(6 Suppl.)
to true b cells than any other cell differentiation product described thus far from adult stem cells [17,18] . Although their maturation still requires a last in vivo step [19] , the screening of compounds with the ability to enhance the differentiation outcome is still yielding very promising results. A number of activators of the PKC pathway [20,21] , as well as TGF inhibitors and other small molecules [22] have been recently reported to improve the differentiation of pancreatic progenitors and insulin-producing cells. Advances towards obtaining a fully functional cell product in vitro are important because of the dangers associated with the transplantation of immature progenitor cells, chiefly the formation of teratomas [23] . A Gartner-like hype curve has also been seen in the readjustment of our expectations for this technology, but the ‘plateau of productivity’ we are currently witnessing is still extremely promising. The California-based company ViaCyte (CA, USA; formerly Novocell) has reported preclinical success with human ES cell-derived pancreatic progenitor cells, which are delivered subcutaneously within an immunoisolation device. The award of more than US$20 million to this project by the California Institute of Regenerative Medicine and the Juvenile Diabetes Research Foundation highlights the current interest in furthering research aimed at having a clinical ES cell-based product for diabetes within the next 5 years. Given the solidity of the reported preclinical data and the fact that ES cells are already in clinical trials for other conditions (e.g., Stargardt’s macular dystrophy and advanced dry age-related macular degeneration), the above timeframe does not appear to be unreasonable (see www.clinicaltrials.gov for additional information on current ES cell trials [101]). By virtue of its overnight success, the direct reprogramming of cells to a pluripotent state is arguably the most surprising and over-reaching discovery future science group
Cellular therapies to tissue reprogramming & regenerative strategies in the treatment of diabetes
this young field has seen thus far [24–31] . The unprecedented speed at which induced pluripotent stem (iPS) cells have become a staple in regenerative medicine laboratories is illustrated by the observation that, barely 5 years after they were first described, the technology has seen the completion of its own Gartner hype curve [32,33] . Indeed, the original excitement about this noncontroversial mix of adult and ES cells has waned significantly in view of some unexpected shortcomings, among them the lingering ‘memory’ of the parental cells from which they came [34] , the worrisome observation that the reprogramming process itself may be accompanied by the induction of genetic mutations associated with the activation of potentially oncogenic events [35–37] , the potential expression of tumor antigens that could mediate the rejection of grafts even from autologous sources [38] or even the premature senescence of their derivatives [39] . On the brighter side, their generation is no longer dependent on the use of translationally unfriendly viruses, which have been progressively replaced by episomal constructs [40] , transducible proteins [41,42] , DNA minicircles [43] , modified mRNAs [44] and even small chemical agents [45] . A b-cell differentiation protocol first designed for human ES cells was adapted to iPS cells by Tateishi and colleagues who, not surprisingly, reported a similar outcome [46] . It still remains to be seen if iPS cells will be of any practical use in the context of T1DM. Unlike nonautoimmune conditions, in which a perfect match between the donor tissue and the recipient would be highly desirable, iPS cell-derived b cells are not likely to fare any better against the faulty immune system of T1DM patients than their original b cells did after the onset of the disease. Given that some form of immunosuppression will be needed anyway, we may as well go for the easier alternative of an off-the-shelf, future science group
fully characterized allogeneic ES cell source, probably in conjunction with physical immunoisolation. If we add to this the more general consideration that ‘patient-tailored’ iPS cell therapies are probably too costly and impractical to even consider at this juncture for even far less complex conditions, we do not anticipate iPS cells to be in the running for the next diabetes therapy breakthrough any time soon.
Better sources of mesenchymal stem cells? The majority of adult stem cells used in the context of regenerative purposes belong to the mesenchymal stem cell (MSC) category. These fibroblast-like cells are abundant in most human tissues [47] , grow well in plastic, and can be readily differentiated into fat, cartilage and bone [48] . There are strong arguments for and against the notion that all MSCs are one and the same. A series of well-defined characteristics that define them as a group [49,50] does not preclude a puzzling variability in their behavior that depends on factors as diverse as their tissue of origin, the age of the tissue, the donor, or even the specific clone analyzed (within the same donor and organ) [51] . Although ES cells are also not precisely known for the homogeneity of their behavior, one must consider that most studies have been done with a handful of cell lines. This is not the case with MSC research, a field in which we would be pressed to find any two groups studying the same MSC clone. This has complicated tremendously the definition of a ‘gold standard’ of differentiation into b cells – a goal that many believe to be unrealistic. Current efforts include standard chemical approaches, genetic manipulation and even in vivo maturation following systemic administration [52–70] . If we add to this the mind-boggling amount of cellular substrates being utilized (spanning from bone marrow and umbilical cord blood to periodontal www.futuremedicine.com
ligament and fat, the latter extracted from numerous anatomical locations, each one yielding cells of seemingly superior properties than the other), it is hardly surprising that no significant breakthroughs have been reported – let alone reproduced – yet. The above limitations notwith standing, at least two sources of MSCs have garnered special attention in recent months. One of them is umbilical cord blood, which is easily bankable [71–74] and offers the theoretical advantage of its ‘youth’. This was one of the conclusions of a recent study by Prabakar et al., who described cord blood-derived MSC cells that exhibited a number of ES cell characteristics and responded similarly to a b-cell differentiation regimen [70] . However, for those who did not have their own cord blood harvested at birth or failed to save those precious baby teeth, not all hope is lost: MSCs are anything but rare in adults. In this context, the second MSC source that currently commands the most attention is the adipose tissue. In particular, some claim that MSCs obtained from eyelid surgery are the best, especially in the context of b-cell differentiation [75] . The proponents of this type of cell contend that they derive from the neural crest, which is known to be home to multipotent cells throughout development [76] . This finding would also be consistent with the purported ability of another neural crest-derived MSC, the periodontal ligament, to differentiate along the three embryonal layers (including insulin-producing cells) [77] . Despite the cautious excitement caused by some of these findings, there is no denying that a breakthrough in b-cell differentiation similar to that already described for ES cells [17–19] appears less likely by the minute. Many thought that the intrinsic limitations of MSCs to differentiate along definitive endoderm (a turn they probably missed for good when they took the mesodermal path) 43
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could be overcome by sheer in vitro manipulation. After all, cells are known to behave in strange ways when taken out of their physiological context. At this point, however, it would seem that MSCs can only be coaxed up to a point, which is nowhere near the phenotype of a true b cell. It was an earnest and wellfought effort, but one that ultimately may only meet with success by means of more drastic phenotype-changing approaches (i.e., reprogramming). Owing to this, we are progressively witnessing a diversion of differentiation studies in favor of research focused on the exploitation of the well-known proangiogenic and immunomodulatory properties of MSCs [78–83] , which are attractive characteristics in their own right and worthy of discussion in a separate review.
Lateral reprogramming The notion of reprogramming is an unlikely one: that a terminally differentiated cell can change its identity. This concept, already explored successfully in the induction of pluripotency, has also proven its worth in the context of b-cell neogenesis. The expression of the PDX1 gene in the foregut around the eighth day of embryonic development in the mouse is a hallmark of pancreatic specification. The role of PDX1 as a ‘master regulator’ in this process has led to the hypothesis that its ectopic expression might be able to induce pancreatic differentiation from various cell substrates. This strategy, however, was largely unsuccessful when tested in a variety of tissues [84–86] , with the exception of the liver [87–90] . Indeed, adenoviralmediated transduction of PDX1 into hepatic tissues in vivo has been shown to reverse hyperglycemia long term [87,88] , chiefly through a process of partial conversion of phenotype from hepatocytes to b cells. However, the fact that such conversion was never full prompted new experiments looking at more ‘master’ genes (which may act 44
synergistically with PDX1) as well as cell substrates even closer than the liver, from a developmental point of view, to the endocrine compartment of the pancreas. The ductal tissue is one such substrate that has shown promising results over the years. Thus, when ductal tissue-rich leftovers of clinical islet preparations were cultured in conditions that foster ductal cell expansion, cells co-expressing ductal and b-cell markers were identified [91] . Adult mouse and human ductal cells transduced with adenoviruses harboring PDX1, PAX4, NGN3 and NEUROD expression cassettes strongly upregulated insulin expression [92] . As recently reported by Zhou and colleagues, the acinar tissue of the murine pancreas can also be ‘reprogrammed’ by ectopically expressing a combination of three genes (PDX1, NGN3 and MAFA) [93] . New insulin-producing cells that were virtually indistinguishable from the native ones sprouted in the parenchymal vicinity of the site of the injection just days after the delivery of the above genes. Blood glucose levels were significantly ameliorated in the treated animals, even if diabetes was not completely reversed. One possible explanation for this observation is that the newly induced cells failed to aggregate, a phenomenon that occurs naturally and is thought to foster cell-to-cell communication and the synchronicity of the glucose-mediated insulin secretion [94,95] . Still, few would dispute that the reported results were nothing short of extraordinary. Inspired in the pioneering work of Ferber and colleagues with ectopic Pdx1 in the liver earlier in the decade [87,88] , the choice of a starting material that was ontogenetically closer to the b cell (the acinar pancreas) turned out to be as critical, if not perhaps even more critical, than the use of the three genes instead of just one. In this case, the reprogramming process completely abrogated the original phenotype of the acinar cells. Despite the lack of additional characterization (glucoseinduced insulin secretion, insulin Regen. Med. (2012) 7(6 Suppl.)
content and gene expression profiles) and the fact that they did not completely revert hyperglycemia in diabetic mice, these cells appeared to be b-like, and not just insulin-secreting exocrine b-cell hybrids. Much remains to be done before this strategy could be clinically applicable. For starters, adenoviruses were used to deliver the three reprogramming factors. Although they are present only transiently, these viruses are known to elicit inflammation and other detrimental immune responses. Of note, the more clinically friendly adenoassociated viruses had previously failed to induce reprogramming in a similar setting [96] , suggesting that some of the perceived shortcomings linked to the use of adenoviruses might paradoxically end up being fundamental for the success of this approach. Be this as it may, these experiments provide the proof of concept that exocrine cell reprogramming is feasible, and perhaps reproducible ex vivo on cultured acinar cells (which, as of today, are routinely discarded after every islet isolation procedure). Considering that more than 90% of the pancreatic cells belong to the acinar compartment, this potential source of b cells cannot be dismissed. In this context, we anticipate an active period of exploration of nonviral alternatives for the delivery of the reprogramming agents, mirroring efforts already reported for ‘vertical’ iPS cell reprogramming.
Future perspective Still in its infancy, the field of b-cell regeneration for the treatment of diabetes has already generated numerous avenues of research. Cellular therapies, stem cell and regenerative strategies are of critical and timely interest for their potential application in all cases of insulin-requiring diabetes, including (but not limited to) T1DM and a large proportion of patients with T2DM, in which b-cell future science group
Cellular therapies to tissue reprogramming & regenerative strategies in the treatment of diabetes
dysfunction and requirements for exogenous insulin treatment would justify a biologic replacement or regenerative therapy. The selection of the most appropriate source for insulin-producing cells is still not defined and the selected alternatives between replacement, reprogramming and regeneration strategies should be further developed in preclinical model systems and tested in pilot clinical trials, while carefully assessing cost–effectiveness and the relative potential for scale-up, so that patients affected by diabetes are given realistic therapeutic options. A prediction about which of these avenues will ultimately become the treatment of choice may turn out to be a futile exercise, and more so because several of the strategies described herein
may end up converging in a unified approach. For instance, we could envision a strategy in which recipientspecific iPS cells are differentiated into b cells in vitro and then cotransplanted with adult MSCs (also isolated from the patient) for improved engraftment and function. On the other hand, we could expand ex vivo candidate tissues from the prospective recipient and then reprogram them laterally into insulin-producing cells for subsequent transplantation. Parallel advances in immune-modulating approaches will undoubtedly foster the ultimate therapy in which the cells that are either replaced or regenerated are protected from the immune system of the patient (allo- and auto-immunity). Careful attention should also be directed to the assessment of the risk/benefit ratio associated with the selected cell product
or regenerative/reprogramming strategy, as well as the possible side effects and risks linked to the immune-modulatory or immune-protective strategy required to avoid the destruction of the transplanted or reprogrammed/ regenerated insulin-producing cells.
Financial & competing interests disclosure C Ricordi, J Domínguez-Bendala and L Inverardi acknowledge funding from the NIH, the Juvenile Diabetes Research Foundation and the Diabetes Research Institute Foundation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
Key points Islet transplantation has set the stage for the next generation of cell therapeutics for Type 1 diabetes. Progress in embryonic stem cell research is likely to be translated into clinical trials for diabetes in the near future. Mesenchymal stem cells are finally finding their ‘niche’ as adjuvants in the process of engraftment and/or endogenous regeneration, rather than as building blocks for new insulin-producing b cells. The advent of ‘lateral reprogramming’ techniques may potentially tap into a plentiful supply of newly generated b cells.
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Website 101 ClinicalTrials.gov
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RESEARCH & DEVELOPMENT
Expert Focus Convergence of gene and cell therapy Alexey Bersenev & Bruce L Levine* Gene therapy and cell therapy have followed similar roller coaster paths of rising public expectations and disappointment over the past two decades. There is now reason to believe that momentum in the field has reached the point where the successes will be more frequent. The use of gene-modified cells has opened new avenues for engineering desired cell properties, for the use of cells as vehicles for gene delivery, and for tracking cells and controlling cell persistence after transplantation. Some notable recent clinical developments in cellular engineering by gene transfer offer lessons on how the field has emerged, and hint at additional future clinical applications. Keywords: cell therapy n clinical trial n gene therapy n immunotherapy
In this article we will review some of the key developments in cell engineering by gene transfer, summarized in Box 1.
Cell gene therapy for correction of genetic disorders The first use of gene-modified cells was for correction of an inherited missing gene function by autologous transplantation of gene-modified hematopoietic stem/progenitor cells (HSPCs). Adenosine deaminase (ADA) deficiency results in a buildup of cellular dATP and prevention of DNA synthesis. Rapidly dividing cells of the immune system and especially T lymphocytes are affected. As a monogenic disease, severe combined immunodeficiency (SCID)-ADA was a prime candidate for gene therapy and the first-in-human studies were performed in the early 1990s [1] . Since that time, approximately 100 transplants of gene-modified CD34 + hematopoietic cells have been performed around the world [2,3] . Long-term observation of patients with SCID-ADA has shown that cellular gene therapy is safe, leads
were able to recover immune function and many have been able to reduce or discontinue enzyme-replacement therapy and significantly improve their quality of life. Long-term follow-up In the last two decades, gene data provides evidence for persistence correction has been clinically tested in of transduced T-cell lineages at least a number of other monogenic blood/ 3–5 years later and even up to 12 years immune disorders, such as X-linked after transplantation [1] . However, some defect in the IL-2 receptor g chain SCID cases of gamma-retrovirus-induced (SCID-X1), chronic granulomatous acute leukemia and myelodysplasia were deficiency (CGD) and Wiskott–Aldrich reported in the SCID-X1 and CGD syndrome. Long-term results of the early trials, respectively [2,3,10] . The T-cell trials, which utilized gammaretrovirus- proliferation seen in the SCID-X1 trial mediated gene therapy in autologous is likely due not only to insertional hematopoietic CD34 + cells in SCID-X1 mutagenesis but also some combination patients, were published recently [6] . of gene insertion to hematopoietic stem Transplantation of autologous gene- cells, the effects of the transgene used transduced CD34 + cells led to in this treatment, and the profound functional correction of immune cells immunosuppressed status of the patients and resolution of clinical symptoms [10] . Although most of the leukemia cases in patients with Wiskott–Aldrich have been successfully treated, it was a syndrome [7] . A number of children big setback for the field. New generations with CGD have been treated by gene- of viral vectors and other approaches to modified hematopoietic cells and showed gene modification of HSPCs are now functional recovery of myelopoiesis and in development and clinical testing to resolution of infections [8,9] . Overall, the improve safety [2,11,12] . These include the early clinical results of cell gene therapy use of self-inactivating retroviral vectors of monogenic immune disorders are and lentiviral vectors [12,13] . A study in very promising. The majority of patients mice comparing the tumorigenicity of to effective immunological and metabolic correction and can be an alternative to conventional HSPC transplantation [1,4,5] .
Alexey Bersenev, Department of Pathology and Laboratory Medicine, The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA *Author for correspondence: Bruce L Levine, Department of Pathology and Laboratory Medicine, The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Tel.: +1 215 573 6788; Fax: +1 215 615 4718; levinebl@mail.med.upenn.edu
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Convergence of gene & cell therapy
retroviral vectors to lentiviral vectors demonstrated that lentiviral vector gene transfer into hematopoietic stem cells was not tumorigenic in contrast to retroviral vectors [14] . While a degree of risk of insertional oncogenesis in HSPCs is likely to remain with currently available gene vectors, the risk of death in patients with SCID-X1 who do not have a tissue-matched donor for HSPC transplantation is unfortunately higher than the observed rate of leukemias in these early gene correction studies.
Redirecting immune cell function One strategy to produce gene-modified cells redirected towards pathogens is the chimeric antigen receptor (CAR) approach first described by Eshhar [15] . CARs express an extracellular ligand generally derived from an antibody and intracellular signaling modules derived from T-cell-signaling proteins (Figure 1 and reviewed in [16,17]). CARs use patientor donor-derived lymphocytes that are gene modified to express chimeric receptor genes. This combines the effector functions of T lymphocytes with the ability of antibodies to recognize surface antigens with high specificity in a non-MHC restricted manner [18] . Thus, universal targeting vectors can be constructed. The first clinical trials of CAR-based T-cell therapy for cancer were reported in 2006; by one group targeting folate receptor in ovarian cancer [19] , and a separate center targeting carbonic anhydrase IX (CAIX) in metastatic renal cancer patients [20] . The CAIX is instructive in that the antigen targeted is overexpressed on renal cell carcinoma, while on normal cells expression is limited to the kidney and the biliary tract. Infusions of the CAIX CAR T cells were initially well tolerated. However, after several infusions most patients developed on-target, off-organ liver enzyme elevations and cellular and humoral immune responses against the CAR and vector [21] . The authors concluded that the liver toxicity was most likely due to the reactivity of CARs against the target future science group
Box 1. Notable developments in the convergence of cell and gene therapy. Correction of a faulty gene and/or missing function The earliest application, and perhaps to this day what the lay public associates with the term ‘gene therapy’ Redirecting cell function Increases the number of cells that can fight disease through gene transfer to redirect and enhance function Engineering HIV resistance Gene transfer of a chimeric enzyme recapitulating a naturally occurring mutation that renders homozygotes highly resistant to the most commonly transmitted tropic strain of HIV Designing cell fate: safety switches & pathotropism Enhanced function is good; uncontrolled enhanced function is not so good. Gene transfer of safety switches adds a measure of control A complement to redirecting target specificity is directing/redirecting cell trafficking or tropism
antigen expressed on normal biliary tract tissue. In children, results from a clinical trial using CAR’s directed to the diasialoganglioside GD2 in refractory neuroblastoma have demonstrated safety of GD2-CARs [22,23] . There are a number of clinical trials testing second-generation CARs that incorporate multiple signaling domains, primarily in CD19 + and CD20 + hematologic malignancies [17] . Early clinical trials assessing CAR T cells against B-cell malignancies yielded somewhat disappointing results, perhaps due to low levels of in vivo persistence. Our center is conducting a clinical trial utilizing the CAR T-cell approach targeting the CD19 antigen in B-cell leukemia and lymphoma (NCT00891215). Figure 2 shows our method for the production of CAR T cells. This was the first trial using lentiviral vector technology in cancer and the first to include the 4–1BB signaling domain. The engineered T cells expanded more than 1000fold in vivo, trafficked to bone marrow and continued to express functional CARs that have persisted at high levels. Preliminary results reported from this trial are promising as three out of three patients with advanced chronic lymphocytic leukemia treated gained clinical benefit, including complete www.futuremedicine.com
remission in two out of the three patients [24,25] . These two patients have a continuing remission at >20 months following CAR infusion and additional patients have recently been treated. CAR T cells have the potential to last many years and provide a memory response against tumor or infection. In a series of trials testing a gp120directed CAR in HIV-positive study subjects, we recently reported decadelong persistence of CAR T cells [26] . This study also indicated the safety of gene-modified T cells. Insertional mutagenesis, which caused leukemia in HSPC-based trials, appears not to be a general feature of gammaretroviral vectors in this cohort with a combined total of >500 years of subject follow-up. Two recent studies have reported fatal serious adverse events following CAR infusion. In a trial testing CAR T cells targeted against CD19 in B-cell lymphoma, one patient demonstrated elevated cytokines that may have been secondary to a prior subacute infection exacerbated by the immune suppression associated with chemotherapy-induced lymphodepletion. This was attributed as the most likely cause of death and ‘possibly related’ to CAR T-cell infusion [27] . The second case was a trial in cancer patients with overexpressing HER-2/neu tumors treated with an 51
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(D32) was described in 1996, which explains why certain high-exposure risk patients remained HIV-resistant [31] . CCR5 was therefore recognized as a potential drug target and several drugs are now approved to block HIV cellular entry. A recapitulation of the naturally occurring mutation was reported in an HIV-positive patient in Berlin diagnosed with leukemia who underwent a HSPC treatment with a matched unrelated donor also selected for the CCR5 D32 mutation [32] . Several years after this treatment, there is no detectable HIV in this patient in multiple biopsied tissues [33] .
Figure 1. T cells can be engineered to have retargeted specificity for Âtumors. Endogenous T cells express a single heterodimeric TCR (left). Chimeric antigen receptor T cells are created by the introduction of genes that encode chimeric tumor antigen-specific receptors, or T bodies, composed of antibody extracellular domains and T-cell-signaling intracellular domains such as 4-1BB and CD3z. Chimeric antigen receptor T cells target surface antigens in an MHC-independent fashion. TCR: T-cell receptor; ZAP70: Zeta-chain-associated protein kinase 70 kDa.
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anti-HER-2/neu CAR [28] . The patient received a lymphodepleting regimen followed by 1010 HER-2/neu CAR T cells. The patient demonstrated a dramatic rise in proinflammatory cytokines, consistent with a cytokine storm, initiating multisystem organ failure. In our study at the University of Pennsylvania (PA, USA), we reported delayed tumor lysis syndrome after CAR T-cell infusion [24,25] , fortunately followed by recovery and remission. These cases point out the potency of this approach and the need for careful design, conduct and monitoring after infusions.
at risk for long-term comorbidities and uniformly exhibit recurrent viremia when antiretroviral therapy is discontinued due its failure to eradicate the viral reservoirs [29] . Cellular gene therapy approaches developed for treatment of HIV include engineering HIV resistance at various points during the HIV infection cycle, the generation of cytotoxic CD8 + TÂ cells expressing HIV-specific T-cell receptors, engineering HIV resistance through ribozymes, combinatorial approaches, and blockade of viral entry into immune cells by engineering HIV-resistant T cells [30] .
Engineering HIV resistance Despite the profound successes of combination antiretroviral drug therapy in HIV, patients remain
Genetic epidemiology has led to the development of strategies to target HIV cellular entry. A naturally occurring mutation of the HIV cellular entry coreceptor CCR5 Regen. Med. (2012) 7(6 Suppl.)
Designer zinc finger nucleases (ZFNs) are chimeric DNA-binding proteins/endonucleases that can edit the genome by targeted DNA doublestrand breaks [34] . We previously showed that engineered ZFNs targeting human CCR5 efficiently generate a double-strand break at a predetermined site in the CCR5 coding region upstream of the natural CCR5 D32 mutation. Transient expression of the CCR5-targeted ZFNs was sufficient to selectively, efficiently and stably modify the CCR5 locus. ZFN-modified T-cells show a marked growth advantage when challenged both in vitro and in vivo with CCR5-tropic HIV [35] . CCR5 ZFN modification in CD4 T cells may render a survival advantage to these cells in HIV-infected subjects. Two clinical trials have been conducted to test the effect of these genome-modified cells on safety, increases in CD4, persistence and trafficking of CCR5 ZFN modified TÂ cells, and effect on HIV viral load (NCT01044654 and NCT00842634). The safety results have been encouraging and additional clinical trials are planned. The development of cell-based engineering approaches inducing robust CD4 + T-cell resistance to HIV infection would be significantly less expensive and less toxic than allogeneic HSPC transplant with a CCR5-/- (D32) donor, and less expensive than a lifetime of antiretroviral drug therapy. future science group
Convergence of gene & cell therapy
Autologous blood collection
Infusion of T-cells
Patient
Antibody-coated beads Cell product Activated expansion gene delivery Bead removal and formulation
Figure 2. Ex vivo process for engineered T-lymphocyte therapies. White blood cells are removed by blood draw or leukapheresis and T cells are stimulated with anti-CD3 and anti-CD28 mAb-coated beads in media supplemented with vector encoding the transgene. Cells are expanded ex vivo for approximately 10 days when beads are removed and the cells are washed, concentrated and formulated to the final cryopreserved cell product. The cells are infused following completion and review of quality control testing.
Safety switches & pathotropism The ability to design and control cell fate after transfusion could prevent complications, such as inefficient migration, excessive proliferation, ontarget but off-tumor immune reactivity and graft-versus-host immune reactions. One current approach to directing cell fate involves the introduction of so-called ‘suicide genes’, which when activated by a drug, lead to elimination of the transduced cells. This approach has been clinically tested in donor T-cell infusions after hematopoietic stem cell transplantation in leukemia. The first future science group
clinical trials involved the gene encoding herpes simplex virus thymidine kinase as a ganciclovir-induced suicide gene [36] . The engineered T cells were controlled by induction of a suicide gene in leukemic patients who had developed graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation and donor lymphocyte infusion. A subsequent trial [37] showed that acute and chronic GVHD could be controlled, and a randomized open-label Phase III trial is in progress (NCT00914628). Another ‘safety switch’ approach has recently been studied where apoptosis www.futuremedicine.com
has been induced in caspase-9 genemodified T cells administered to patients with GVHD [38] . A single infusion of the apoptosis inducer AP1903, an otherwise bioinert smallmolecule dimerizing drug, led to rapid elimination of 90% of transduced T cells with resolution of GVHD. A different safety strategy is to generate chimeric antigen receptor-targeted T cells using RNA [39] . This approach avoids the use of integrating vectors and the potential for genotoxicity, reduces the costs associated with retroviral and lentiviral vector production and testing, 53
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and results in self-limiting expression lasting only several days in vivo. This platform provides a relatively fast, inexpensive and potentially less toxic way to test new construct designs and therapeutic targets. A clinical trial of RNA-modified T cells redirected toward mesothelin is currently underway in mesothelioma (NCT01355965). Some cells, such as mesenchymal stromal cells and neural stem cells, have the ability to specifically migrate to an inflamed area or a tumor, described as ‘pathotropism’. This ability has been exploited to selectively deliver a therapeutic gene to metastatic solid tumors in animal experiments [40,41] . Based on pathotropism, genetically engineered stem cells could be used as a vehicle to deliver a gene encoding an enzyme that can convert a nontoxic prodrug into a toxic agent and, therefore, mediate killing of the tumor mass [42] . Genetically modified neural stem cells that convert 5-fluorocytosine into the chemotherapeutic agent 5-FU are undergoing clinical trials in patients with gliomas (NCT01172964). Cell migration may be engineered in combination with any of the approaches discussed above to improve homing and engraftment and engineered cells [43] .
Future perspective From the initial idea of gene therapy as gene correction, proof-of-concept has now been demonstrated in a number of gene-modified cellular therapy approaches. The development of improved vectors and gene transfer technologies, along with improvements to ex vivo culture systems have enabled the field to blossom into a multiplicity of applications in a wide variety of diseases. What began as elegant simplicity has now evolved into the creative combination of a variety of gene and cell engineering technologies. The next step in gene and cell therapy will be to move more of these technologies into later-stage clinical trials and subsequent regulatory approval. This type of ex vivo genetic manipulation and adoptive therapy is most often autologous or directed, and is a different paradigm in drug development compared with biologics or allogeneic cell therapies. Clinical and commercial development of these technologies requires ‘outscaling’ and strict chain of custody practices. In the nearer term, one can speculate that the first approved genetically modified cell products will be developed for clear unmet medical needs and orphan indications, such as many of the monogenic
diseases. Alternatively, products that demonstrate efficacy where repeated courses of other conventional therapies have failed will spur investment, development, regulatory approval, and commercialization. Within these diverse environments, gene and cell therapy has demonstrated the conversion of innovation into new therapies to treat our patients.
Acknowledgements The authors would like to thank Anne Chew for thoughtful advice.
Financial & competing interests disclosure Bruce Levine has financial interest due to intellectual property and patents in the field of cell and gene therapy. Conflict of interest is managed in accordance with University of Pennsylvania policy and oversight. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
Key points Gene-modified hematopoietic cells can correct a faulty gene and/or missing function. Gene modified cells or their progeny can persist for decades. Immune cells can be redirected to tumor or other antigens through the delivery of genes encoding chimeric antigen receptors. Gene transfer and ex vivo expansion of the modified cells increases the number of cells that can fight disease, redirects and enhances immune cell function. Immune cells that are the target of HIV infection can be genetically edited to remove the most common coreceptor that HIV needs for cellular entry. This mimics a naturally occurring mutation that renders homozygotes highly resistant to the most commonly transmitted tropic strain of HIV. Ex vivo gene transfer of safety switches adds a measure of control to genetically modified and adoptively transferred cells. Recent work aims to control and direct cell trafficking or tropism for targeted delivery of a modified cell or prodrug.
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Evidence for the cure of HIV infection by CCR5Delta32/Delta32 stem cell transplantation. Blood 117(10), 2791–2799 (2011). 34 Urnov FD, Miller JC, Lee YL et al. Highly
efficient endogenous human gene correction using designed zinc-finger nucleases. Nature 435(7042), 646–651 (2005). 35 Perez EE, Wang J, Miller JC et al.
Establishment of HIV-1 resistance in CD4 + T cells by genome editing using zinc-finger nucleases. Nat. Biotechnol. 26(7), 808–816 (2008). 36 Tiberghien P, Ferrand C, Lioure B et al.
Administration of herpes simplexthymidine kinase-expressing donor T cells with a T-cell-depleted allogeneic marrow graft. Blood 97(1), 63–72 (2001). 37 Ciceri F, Bonini C, Stanghellini MT et al.
Infusion of suicide-gene-engineered donor lymphocytes after family haploidentical haemopoietic stem-cell transplantation for leukaemia (the TK007 trial): a nonrandomised Phase I–II study. Lancet Oncol. 10(5), 489–500 (2009).
39 Zhao Y, Moon E, Carpenito C et al.
Multiple injections of electroporated autologous T cells expressing a chimeric antigen receptor mediate regression of human disseminated tumor. Cancer Res. 70(22), 9053–9061 (2010). 40 Yin J, Kim JK, Moon JH et al. hMSC-
mediated concurrent delivery of endostatin and carboxylesterase to mouse xenografts suppresses glioma initiation and recurrence. Mol. Ther. 19(6), 1161–1169 (2011). 41 Joo KM, Park IH, Shin JY et al. Human
neural stem cells can target and deliver therapeutic genes to breast cancer brain metastases. Mol. Ther. 17(3), 570–575 (2009). 42 Kim SU, Jeung EB, Kim YB, Cho MH,
Choi KC. Potential tumor-tropic effect of genetically engineered stem cells expressing suicide enzymes to selectively target invasive cancer in animal models. Anticancer Res. 31(4), 1249–1258 (2011). 43 Sarkar D, Spencer JA, Phillips JA et al.
Engineered cell homing. Blood 118(25) e184–e191 (2011).
38 Di Stasi A, Tey SK, Dotti G et al. Inducible
apoptosis as a safety switch for adoptive cell therapy. N. Engl. J. Med. 365(18), 1673–1683 (2011).
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ADVOCACY & EDUCATION
Article type
INDUSTRY, COMMERCIALIZATION & COLLABORATION
INDUSTRY Highlights Interviews Researchers and the translational reality Karen Aboody The Regenerative Medicine Coalition Frank-Roman Lauter
Commentary Collaborations in Stem Cell Science Jonathan Thomas
organization profile The International Translational Regenerative Medicine Center Mardi de Veuve Alexis, Karl-Henrik Grinnemo & Richard Jove 10.2217/RME.XX.XX © 2011 Future Medicine Ltd
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INDUSTRY, COMMERCIALIZATION & COLLABORATION
Stem cell and regenerative medicine
September 1, 2011–August 31, 2012
Business Development » Winning on multiple fronts: Cellular Dynamics International Cellular Dynamics International, WI, USA (www.cellulardynamics.com), continued its domination in the area of induced pluripotent stem cells. In addition to its portfolio of iCell® products, human-induced pluripotent stem cell-derived cardiomyocyes, neurons, hepatocytes and endothelial cells, the company launched the new service MyCell™. MyCell is offering cell reprogramming, genetic engineering and cell differentiation from customers’ samples. Cells from a variety of tissue sources can be reprogrammed with genome nonintegrating episomal vectors under feeder-free conditions. In October 2011, the company was named as the overall Gold winner in The Wall Street Journal Technology Innovation Awards by a panel of independent judges among 605 contestants in 16 categories.
» The thunder from Down Under: Mesoblast Following acquisition of the USA company Angioblast and a strategic alliance with Cephalon, now wholly owned by Israel-based Teva Pharmaceutical Industries; www.tevapharm.com), Australia-based Mesoblast (www.mesoblast.com) has strengthened its position even further. In September 2011, Mesoblast formed a strategic alliance with Lonza for clinical and long-term commercial production of Mesoblast’s allogeneic adult stem cell products. The alliance will provide Mesoblast with significant commercial advantages, including certainty of capacity to meet long-term global supply of its proprietary mesenchymal precursor cell products; a purpose-built manufacturing facility to be built by Lonza exclusively for Mesoblast and exclusive access to Lonza’s cell therapy facilities in Singapore. Mesoblast has been granted approval to conduct clinical trials of adult stem cell therapies for a number of conditions, including congestive heart failure, heart attacks, spinal fusion and bone marrow regeneration. The company is progressing various products towards Phase III trials. Dusko Ilic, Human Embryonic Stem Cell Laboratories, Guy’s Assisted Conception Unit, Division of Women’s Health, King’s College London School of Medicine; dusko.ilic@kcl.ac.uk
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Clinical trials » Making history
Advanced Cell Technology’s (MA, USA; www.advancedcell.com) clinical trials in Stargradt’s and age-related macular degeneration so far look to be a success. Preliminary data published in the Lancet in January 2012 demonstrated the safety of human embryonic stem (hES) cellderived retinal pigment epithelial (RPE) cells for the treatment of one patient with Stargradt disease and one with dry age-related macular degeneration. No abnormal proliferation of the cells, no tumor formation or any other adverse effects were noted after the transplantation. Visual improvement was also noted. Less than a year since the first two patients were injected with 50,000 RPE cells in one eye at the Jules Stein Eye Institute at the University of California, Los Angeles (www.jsei.org), the first cohort of US patients with d r y age-related macular degeneration was completed.
The promising preliminary results from the first cohort have positioned the Company well as they entered the second cohort and higher dosage in this landmark clinical trial. The first patient of the second cohort was administered 100,000 RPE cells at Wills Eye Institute in Philadelphia (PA, USA; www.willseye.org) on August 1 2012. In parallel, the second and the third patients with Stargradt’s disease of the first cohort in European clinical trials were treated at Moorfields Eye Hospital in London (UK). The Phase I/II trial is designed to determine the safety and tolerability of hESC-derived RPE cells following subretinal transplantation in patients with Stargradt’s disease at 12 months, the study’s primary end point. It will involve a total of 12 patients, with cohorts of three patients each in an ascending dosage format (50,000–200,000). It is similar in design to the US trial for Stargradt’s disease that was initiated in July 2011. Additional information about these clinical trials can also be found at www. clinicaltrials.gov (ID: NCT01345006, NCT01344993 and NCT01469832).
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The Phase I/II trial is designed to determine the safety and tolerability of human embryonic stem cellderived retinal pigment epithelium cells following subretinal transplantation in patients with Stargradt’s disease at 12 months, the study’s primary end point.
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Industry highlights
» Into the clinic In May 2012, a human mesenchymal stem cell therapy product Prochymal® (remestemcel-L), produced by Osiris Therapeutics, MD, USA (www.osiris. com) received market authorization from Health Canada for the treatment of acute graft-versus-host disease (GVHD) in children. New Zealand’s medical regulatory agency, Medsafe, voiced their approval a few weeks later. It is also the only stem cell therapeutic currently designated by the US FDA as both an orphan drug and fast track product.
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Nearly 10,000 doses can be manufactured from a single donation using proprietary isolation and amplification procedures.
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Prochymal’s stem cells are derived from the bone marrow of prescreened healthy donors aged 18–30 years. The health of the donors is monitored for up to 5 years after donation to further ensure their health status. The freshly isolated human mesenchymal stem cells from the bone marrow aspirate are subjected to initial quality control testing for the stem cell potential and safety of the donor before further manufacturing. The in-process intermediate then undergoes further manufacturing to yield a final product, which must pass stringent criteria before release and distribution. Nearly 10,000 doses can be manufactured from a single donation using proprietary isolation and amplification procedures. The Company has 49 issued US patents, each having one or more foreign counterparts. Prochymal is currently being evaluated in clinical trials for the following indications: treatmentresistant, moderate-to-severe Crohn’s disease (www.clinicaltrials.gov ID: NCT00482092), steroid-refractory
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acute GVHD (ID:NCT00366145 and NCT00759018) and, in combination with corticosteroids, newly diagnosed acute GVHD (ID:NCT00562497). All four are Phase III clinical trials. Treatment of recently diagnosed Type 1 diabetes mellitus (ID:NCT00690066) and acute myocardial infarction (ID:NCT00877903) are Phase II clinical trials. All clinical trials are ongoing in multiple centers throughout USA, and some of them also in Canada, Europe and Australia. In addition, Osiris has partnered with Genzyme Corporation, MA, USA (www.genzyme. com), which was acquired in 2011 by French giant Sanofi (www.sanofi.com), to develop Prochymal as a medical countermeasure to nuclear terrorism and other radiological emergencies. Osiris’s division of biosurgery also made an important milestone. The Center for Medicare & Medicaid Services (CMS; www. cms.gov), for Americans 65 years and older, issued a transitional pass-through status with C– Codes being designated for Grafix®. CMS also issued a preliminary positive decision for the assignment of permanent Healthcare Common Procedure Coding System Q–codes for Grafix. The codes will assist in facilitating reimbursement when Grafix products are used to treat Medicare patients with acute and chronic wounds, especially diabetic foot ulcers, in the hospital outpatient department and ambulatory surgical center settings. This coverage decision will boost investor confidence in Osiris’s portfolio of stem cell-based therapeutics.
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This ruling means that from a legal point of view stem cells are treated as drugs if they have been subjected to more than minimal manipulation.
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Regulations » No way out In July 2012, The US District Court in Washington, DC ruled that the FDA has the authority to regulate autologous stem cell therapies. This ruling means that from a legal point of view stem cells are treated as drugs if they have been subjected to more than minimal manipulation. The court’s ruling was on a legal challenge brought
by Regenerative Sciences, CO, USA (www.regenexx.com) when the FDA sought an injunction to take their product Regenexx™ off the market. The company claimed that the FDA should not be involved in monitoring and regulating Regenexx because the cells were minimally manipulated and all processing has been done in
Colorado. Therefore, the procedure should be considered routine medical practice and be subjected to state law. To avoid strict FDA regulatory monitoring, it is thought that, following this ruling, US stem cell companies offering similar type of services may move to states with lesser regulations.
Capital market and finances » Successful ride on government funding Privately held, venture capital-backed Cellerant Corporation, CA, USA (www.cellerant.com), continued its successful ride on government funding. In September 2011, the Company received US$16.7 million by the Biomedical Advanced Research and Development Authority in the 62
Office of the Assistant Secretary for Preparedness and Response of the Department of Health and Human Services, for the advanced development of CLT-008, a first-inclass, allogeneic, cell-based therapy for the treatment of acute radiation syndrome. This funding is in addition Regen. Med. (2012) 7(6 Suppl.)
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Industry highlights
to the existing contract valued at up to US$153.2 million previously awarded in September 2010. Under the terms of this revised contract, Cellerant will receive up to $80 million in the 2-year base period of performance and up to an additional US$89.9 million in 3 option years, if exercised by Biomedical Advanced Research and Development Authority, bringing the total value of the contract to US$169.9 million.
Cellerant’s CLT-008 cell therapy product contains only early- to late-stage myeloid progenitor cells, which have lost the ability to self-renew and are restricted to creating mature myeloid cells: red blood cells, platelets, granulocytes and macrophages. They cannot create lymphoid cells, including the T cells that cause GVHD. Once infused, CLT-008 myeloid progenitor cells create a burst of mature cells and then die and clear out of the system in approximately 45 days.
» Xeno-cell therapy attracting investments Australia/New Zealand-based Life Cell Technologies (www.lctglobal. com), secured a major pharmaceutical partner, Japanese giant Otsuka Pharmaceutical Factory (www. otsukakj.jp/en/), for co-development of its product DIABECELL® through Phase II and other pivotal studies, aiming for marketing by 2016. Life Cell and Otsuka formed a joint venture in November 2011, Diatranz Otsuka Ltd, with each partner owning a 50% share in the new company. With development funding secured for DIABECELL, Life Cell is poised to further develop its second xeno-cell
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therapy product NTCELL® aimed for treatment of Parkinson’s disease. Treatment with NTCELL involves transplanting pig choroid plexus cells into the brain. Choroid plexus cells secrete neurotrophic factors vital to the health and survival of brain tissue. The goal of the transplanted cells is to boost neurotrophin production and so help to protect, repair and possibly regenerate brain and nerve tissue. Both DIABECELL and NTCELL are encapsulated with IMMUPEL™, Life Cell’s proprietary encapsulating technology, eliminating the need for immunosuppressant drugs.
www.futuremedicine.com
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With development funding secured for DIABECELL®, Life Cell is poised to further develop its second xeno-cell therapy product NTCELL® aimed for treatment of Parkinson’s disease.
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INDUSTRY, COMMERCIALIZATION & COLLABORATION
Interview Researchers and the translational reality
Interview with Karen Aboody Karen Aboody has first-hand experience of taking a potential therapy from the laboratory into clinical trials. Here, she shares with us the challenges and rewards of going from bench to bedside, and why all biomedical researchers need to know what it takes to make the transition if they want the best chance of seeing their discoveries used to help patients.
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How did you first become involved in stem cell research? I was working in the neurogenetics laboratory of Dr Xandra Breakefield at Massachusetts General Hospital, Harvard Medical School in Boston (MA, USA). She was one of the leaders in gene therapy so I got involved in running the preclinical HSV-TK gene therapy trials for glioma – the most aggressive type of brain tumors. One of the reasons the gene therapy clinical trials failed was that the cells implanted did not move away from the injection sites, so they could not deliver their therapeutic payload to all of the tumor cells that were invading into normal brain. They just treated the area in the
immediate vicinity of the injection site. We needed a delivery vehicle that could migrate to target the residual tumor sites and invading cells. Dr Evan Snyder had shown that neural stem cells (NSCs) could localize to injury in the brain, such as stroke. When his best friend got diagnosed with a glioma, he brought neural stem cells to Dr Breakefield’s brain tumor laboratory. I was in the right place at the right time, and took advantage of this opportunity to study these stem cells in more detail. We asked ourselves, if NSCs could migrate to sites of injury, would they migrate to sites of cancer as well? That led to our breakthrough studies, published in Proceedings of the National Academy of Sciences in 2000, demonstrating that
Karen Aboody received her MD at Mount Sinai School of Medicine, and completed her post-doctoral training in Molecular Neurogenetics at Massachusetts General Hospital, Harvard Medical School. After gaining experience in pathology, gene therapy and biotechnology, she joined City of Hope (COH) in 2003 to head a translational research laboratory focused on therapeutic stem cell applications for invasive and metastatic solid tumors. In 2010, she received US FDA approval for a first-in-human clinical trial for neural stem cell-mediated therapy for high-grade glioma patients. This Phase I study is ongoing at COH, supported by NCI/NIH funding. In 2010, she received an US$18 million California Institute of Regenerative Medicine Disease Team Award to develop a second-generation enzyme/prodrug stem cell-mediated brain tumor therapy for clinical trials that may also have applications for other metastatic cancers. Honors include the 2000 AANS Young Investigator Award, and 2008 ASGCT Outstanding New Investigator Award. She recently founded a clinical-stage biopharmaceutical company, TheraBiologics Inc., to support clinical development of neural stem cell-mediated cancer therapies. 64
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NSCs had an inherent ability to target cancer sites in the brain and invasive tumor cells – even when they were injected at a distance from the tumor [1] . Once this was clearly demonstrated, we began to consider the best payloads the NSCs could deliver to the tumor cells – to localize the chemotherapy selectively to the tumor sites and minimize toxicity to normal tissues, reducing chemotherapy-associated side effects. What is the main focus of your research at City of Hope? NSC-mediated cancer therapy focused on translation from the bench to the clinic. Our lead studies are using the NSCs to deliver various therapeutic payloads to brain tumors, including glioma, medulloblastoma and solid tumor metastases to the brain. We are also investigating intravenous administration of NSCs to treat metastatic cancers, including neuroblastoma, breast carcinoma and colon cancer. In addition to safety and efficacy studies, we are also trying to determine the specific signals involved in the stem cell–tumor tropism, to understand the mechanisms involved in the tumor-targeting ability of the NSCs. In November 2010, City of Hope initiated a Phase I clinical trial using NSCs to deliver targeted chemotherapy to patients with brain tumors. Tell us a bit more about the trial design and end points. This first-in-human stem cell-mediated cancer trial was designed as a safety/ feasibility study to treat recurrent highgrade glioma patients. These patients have failed chemotherapy, surgery and radiation, and have a grim prognosis of less than 6 months survival. We are testing four escalating doses with a total of up to 20 patients. Our NSCs are engineered to produce an enzyme (cytosine deaminase) that will activate a prodrug (5-fluorocytosine) to an active chemotherapeutic agent (5-fluorouracil). future science group
The stem cells are injected into the brain tumor site at the time of surgical resection or biopsy. We expect the NSCs to migrate through brain tissue and localize to residual tumor sites and invasive tumor cells. The patient is then treated for 7 days with the prodrug. When the drug reaches the brain, the stem cells will activate it to the chemotherapeutic agent locally at the tumor site, in essence targeting the therapy selectively to the tumor cells. This targeted therapy should greatly reduce toxicity to normal tissues and chemotherapy-associated adverse side effects. Currently, only one round of NSCs + prodrug treatment is being conducted. Once the Phase I study is completed we hope to give multiple rounds of treatment and open the trial to patients with secondary brain tumors – patients with brain metastases from primary breast cancer, lung cancer and melanoma – in addition to glioma patients. Importantly, in 2010 we also received a US$18 million Disease Team Award from the California Institute of Regenerative Medicine to develop a second generation of therapeutic NSCs to clinical trial by 2015. The same NSCs in the current Phase I trial are further modified to deliver a carboxylesterase enzyme that will convert irinotecan to its activated form SN-38 – a chemotherapy agent that is 1000-times more potent for tumor killing than irinotecan alone. This strategy may have potential applications for other types of cancers in addition to brain tumors [2] .
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Our aim is to scale‑up manufacture and production of our cells and open a multicenter Phase II trial. This would be a multidose trial for patients with recurrent high-grade glioma as well as solid tumor brain metastases.
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Tell us a bit more about TheraBiologics Inc.: what led you to found the company? I founded the company [101] last year to ensure funding for clinical development of this therapy, and keep it moving forward. I learned that, ultimately, industry must step in to cover the huge costs of Phase II–III clinical trials, as hundreds of millions of dollars are needed to move a therapeutic technology to commercial product. If www.futuremedicine.com
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one cannot get funding for this clinical development, the technology is ‘dead on the vine’ no matter how promising it may be. As idealistic as I was, I had to face the true facts – money matters. What are the key milestones for the company over the next 5 years? Our aim is to scale-up manufacture and production of our cells and open a multicenter Phase II trial. This would be a multidose trial for patients with recurrent high-grade glioma as well as solid tumor brain metastases. We also plan to raise enough capital to fund upcoming Phase I trials using further modified NSCs to deliver two different therapeutic payloads. These trials are planned to start in 2015. How important is it for biomedical scientists to be aware of the potential to translate their work? It is extremely important to examine our scientific discoveries from the laboratory and determine how they might be applied for clinical use. Ultimately, we want to help the patients. The more understanding we have of the disease processes, the more potential targets are elucidated for treatment strategies to be developed and applied. Support and attention need to be given to translational scientists, who form the bridge between basic research and clinical research.
The process involves a collaborative team effort, including researchers, clinicians, GMP manufacture and regulatory affairs. I believe it is important for scientists to think even beyond clinical trials; I encourage my post docs to get some industry experience. Researchers and clinicians are not trained for translational research, it is a process you have to learn. I recently wrote an article with Dr Sally Temple that highlights the process of translating stem cell therapies to the clinic, including the funding and regulatory obstacles, and resources available [3] . What do you see as the greatest challenges for basic scientists entering the translational arena? To team up with translational and clinical researchers, and gain a new perspective – to start thinking how their discoveries can be applied toward disease treatment and prevention. Basic scientists want to understand the how and why of the disease process. Clinicians want what works to treat their patients. Translational research bridges the two and involves a team effort. What was the best advice you were given and what advice would you give other scientists making this transition? When I first came to City of Hope, which is an ideal environment for
translating research from the bench to the bedside, my Chair asked me, “What is your vision? If you could do anything you wanted here – what would you do?” That gave me the space to think big – I wanted to move my research to clinical trial but I did not know how. City of Hope supported me with a team of colleagues, clinicians, manufacturing and regulatory experts to reach my goals. My advice would be: do not give up – do not get discouraged by negative comments from others. We are breaking new ground with potential stem cell treatments, for which there is no precedent. New concepts will always draw criticism and skepticism. Keep your eye on your goals, trust your gut, and just keep moving forward. Others will soon join you.
Financial & competing interests disclosure K Aboody is an officer and founder and director of TheraBiologics Inc., a clinical-stage biopharmaceutical company that she founded in 2011 to advance stem cell-mediated cancer therapies. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
References 1
2
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Aboody KS, Brown A, Rainov NG et al. Neural stem cells display extensive tropism for pathology in adult brain: evidence from intracranial gliomas. Proc Natl Acad. Sci. USA 97(23), 12846–12851 (2000). Aboody KS, Najbauer J, Danks MK. Stem and progenitor cell-mediated tumor
selective gene therapy (review). Gene Ther. 15, 739–752 (2008). 3
Aboody K, Capela A, Niazi N, Stern JH, Temple S. Translating stem cell studies to the clinic for CNS repair: current state of the art and the need for a Rosetta Stone. Neuron 70(4), 597–613 (2011).
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Website 101 Therabiologics
www.therabiologics.com
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INDUSTRY, COMMERCIALIZATION & COLLABORATION
Interview The Regenerative Medicine Coalition
Interview with Frank-Roman Lauter Frank-Roman Lauter, Secretary General of the recently launched Regenerative Medicine Coalition, explains how the coalition was formed and what they hope to achieve.
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Briefly, what is the Regenerative Medicine Coalition? The Regenerative Medicine Coalition (RMC) is a working network, a consortium of leading international translation centers in the field of regenerative medicine. Our mission is to accelerate therapy development in regenerative medicine. How did you get involved and what is your role within the coalition?
In February last year, together with Chris Mason (UCL, London, UK) and Greg Bonfiglio (Proteus Venture Partners, CA, USA), I organized an executive workshop in Berlin on collaborative technology development in the field of regenerative medicine. We invited about 30 key opinion leaders from industry, public/ private funding organizations, academia and translational centers, to discuss how to achieve more efficient (and more cost efficient) product development in the area of regenerative medicine. What kind of environment is needed? What kind of infrastructure? A special interdisciplinary infrastructure is needed to boost the development of new therapies in our field. Existing translational centers provide this infrastructure that bridge ‘bench to bedside’. They are ideal interfaces 10.2217/RME.12.86 © 2012 Future Medicine Ltd
between academia and industry. During the workshop we decided that it would be beneficial to improve communication and collaboration between the various translational centers in our field on an international level, avoiding the repetition of mistakes, sharing knowledge and infrastructure, helping to raise the profile of our member translational centers and collaborating on joint projects.
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[Regenerative Medicine Coalition’s] mission is to accelerate therapy development in regenerative medicine.
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Together with the heads of a number of translational centers, we cofounded RMC. I am serving as the first Secretary General of the coalition at our headquarters in Berlin (Germany). I am responsible for the operational business of the coalition. What are the key aims of the coalition over the next few years? First, we want to establish an efficient collaboration infrastructure between the member translation centers – we want to establish a fixed communication Regen. Med. (2012) 7(6 Suppl.), 69–70
Frank-Roman Lauter has served as Secretary General of the Regenerative Medicine Coalition since 2012, and as Head of Business Development at Berlin-Brandenburg Center for Regenerative Therapies since 2007. Frank-Roman Lauter’s interest is the organization of academic infrastructures to promote efficient translation of research findings into new therapies. He co-organizes joined strategy development for regenerative medicine clusters from seven European countries (FP7-EU Project) and has initiated cooperation between the California Institute for Regenerative Medicine and the German Federal Ministry for Education & Research, resulting in a joined funding program. Recently, he cofounded the international consortium of Regenerative Medicine translational centers (RMC; www.the-rmc.org). Trained as a molecular biologist at the MaxPlanck Institute in Berlin-Dahlem and at Stanford, he has 16 years of experience as an entrepreneur and life science manager in Germany and the USA.
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By facilitating the identification and execution of joint projects and providing due diligence services for those joint projects early on, the RMC will help to de-risk projects [and] lower the hurdle for public and private investors to participate in regenerative medicine therapy development. schedule, with monthly video conferences, biannual workshops and meetings. We will also be looking for other translational centers that complement the existing co-members, in terms of expertise and territory. Currently, we have seven members from translational centers who make up our core membership but we would like to expand that to 12 by the end of this year. For example, so far we have no Asian members in our coalition so that is something we would like to rectify. Second, we are working on compiling and prioritizing technological bottlenecks that are holding off the field. In our consortium, we plan to jointly address those bottlenecks and provide new technological solutions. In addition, the RMC plans to engage in joint therapy development projects. We want to organize additional public and private funding to execute those joint projects and become a major contact point for industry wanting to collaborate on projects for regenerative medicine. Within our translational centers we are able to execute projects from a blank piece of paper through to proof-of-concept Phase I/IIa clinical trials. The RMC also plans to raise additional money that will allow us to invest in validation studies, bridging the ‘valley of death’ and bringing projects to a point where they become very attractive for investors. What will be the coalition’s role in relation to other regenerative medicine organizations (e.g., Alliance for Regenerative Medicine)?
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The RMC is focused on the execution of joint technology development and its core is a working network of translational centers in regenerative medicine. Organizations such as the Alliance for Regenerative Medicine mainly focus on issues of regulation, reimbursement and policy. All of those are very important to create a receptive environment for new regenerative medicine solutions, allowing those new therapies to reach patients quickly and safely. So I believe that the RMC and Alliance for Regenerative Medicine will complement each other nicely. What will the benefits be for those joining the coalition? There will be three types of members: core members, industry members and associated members. The main benefit for the core members is an opportunity for efficient technology development. It also gives them access to larger expertise pools for knowledge and ideas sharing, and provides the critical mass to realize joint projects. Some major projects might not be achievable by one translational center alone, but if two or three join forces, much bigger projects become possible. For the industry members, the benefit is an opportunity to have input into research and development directions that go into translation and on standards that have to be fulfilled. They will have a first look at new technologies, and be able to access translational infrastructure and resources.
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For associate members, public and private funding organizations, it is an opportunity to support RMC in economic development. Projects from translational centers will eventually be licensed to industry or spin-off into start-up companies, so they will create new economic growth. Investors will have access to an international pool of leading experts in the field. By facilitating the identification and execution of joint projects and providing due diligence services for those joint projects early on, the RMC will help de-risk projects. The RMC will help to lower the hurdle for public and private investors to participate in regenerative medicine therapy development. What will be the process for organizations wanting to join the coalition? We welcome other translational centers as well as industry and public/private funding organizations to join the RMC. Shortly, we will post RMC’s future membership policy on our website (www.the-rmc.org) making it easy for additional members to join our consortium.
Financial & competing interests disclosure F-R Lauter is serving as the Secretary General for the RMC. He does not receive any salary for this function in the RMC. He is employed by the Helmholtz-Zentrum Geesthacht, Centre for Biomaterial Development and works at the Berlin-Brandennburg Center for Regenerative Therapies at Ca mpus Cha rité Vichow, Augustenburger Platz 1, 13353 Berlin, Germany. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
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INDUSTRY, COMMERCIALIZATION & COLLABORATION
Commentary Collaborations in stem cell science Jonathan Thomas* Increasingly, the name of the game in stem cell science is collaboration. This takes many forms. We at the California Institute for Regenerative Medicine (CIRM) feel strongly that scientists from academia and industry, both within and outside California, can frequently achieve more by working together than they can by going it alone. From the outset, we have emphasized this notion and are gratified to see so many teams that we have funded working together in the midst of exciting scientific advances on both a national and even international level. This article highlights CIRM’s collaborative strategies and brings you up to date on the extent of our program in this regard. Since inception, the California Institute for Regenerative Medicine (CIRM) has set out to fund projects along the product development spectrum, from basic research through early translation and preclinical work to Phase I/II clinical trials. In the latter portions of that pipeline, to date, we have funded 75 awards, 38 currently incurable diseases and conditions and 23 different academic institutions or biotechnology companies. These awards total more than US$590 million, with more likely through new awards to be made in the coming months. Diseases or conditions covered include heart/blood disease, diabetes, cancer, HIV/AIDS, a host of neurological disorders, blindness, bone/cartilage conditions, skin disease and liver disease, among others. These awards have produced exciting interim results, with many projects on their way to the clinic. With all our awards, but particularly the largest ones, collaboration is key. These awards, dubbed ‘Disease Team’ awards, bring together scientists with a wide variety of skills and areas of expertise to tackle the target disease or condition in question. In many instances, team members come from different institutions or companies within California. Other teams include
members from outside California (both domestic and international). These are our so-called ‘Collaborative Funding Partners’. More on them later. Our first round of Disease Teams were awarded in October 2009. There were 14 awards in all, totaling $225 million from CIRM and another $43 million from two of our international partners. A couple of those awards are illustrative of collaboration in action. Irving Weissman, Director of the Institute for Stem Cell Biology and Regenerative Medicine at Stanford University is teaming up with Paresh Vyas of the Weatherall Institute of Molecular Medicine at Oxford University in the UK to generate a monoclonal antibody that destroys leukemia stem cells. And Dennis Slamon, of the Jonsson Comprehensive Cancer Center at UCLA, CA, USA is partnering with Tak Wah Mak, of the University Health Network in Canada to develop drugs that destroy the cancer stem cells in solid tumors. Beginning in 2008, in response to increasing interest in multinational stem cell research teams, CIRM initiated the Collaborative Funding Program. The concept here was simple. Under Proposition 71, we cannot fund scientists outside California. We can, however, work with such scientists if their part of
*Author for correspondence: Jonathan Thomas, Chairman, The California Institute for Regenerative Medicine, 210 King Street, San Francisco, CA 94107, USA; jthomas@saybrook.net
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the cost is picked up by their sponsoring jurisdiction. Under the terms of the Collaborative Funding Program, a scientist from outside California can join with an in-state scientist to submit a grant in response to a particular Request for Applications issued by CIRM. That team and project would be subject to the same rigorous peer review by our Grants Working Group as all other grants in that round. If that project is ultimately recommended for funding and approved as such by our Board, CIRM would pick up the costs for the California scientist(s) in the team while the other sponsoring entity would pick up the costs for its scientific team. While the concept here is simple, the logistics may not be. All Collaborative Funding Agreements take time to negotiate. Each counter party has its own political and regulatory frameworks to deal with. Some agreements are finalized in a matter of weeks or months. Others have taken many months or years. Still others are yet to be finalized and remain works in progress, notwithstanding everyone’s interest in getting them done. Separate from the logistics, different counterparties have different amounts of money to fund such things as stem cell research. These funding disparities reflect both a given counter party’s emphasis on the research itself, preference given to academia over industry (or vice versa)
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Thomas
and/or the economic realities of the times. Both logistics and funding factor heavily into the Collaborative Funding negotiations. CIRM places great emphasis on its collaborative funding program. Beginning with its first collaborations with Canada and the Australian state of Victoria in 2008, we now have 20 partners. Of those, 13 are countries: Argentina, Australia, Brazil, Canada, China, France, India, Germany, Japan, Scotland, Spain, the UK and USA through the NIH. Several are foundations: New York Stem Cell Foundation, Juvenile Diabetes Research Foundation, the ALS Foundation and the Muscular Dystrophy Association. The balance are states, both within the USA and in other countries, such as Maryland, Victoria (Australia), and Andalucia (Spain). These collaborations have led to 26 ongoing research projects with several more likely to be funded later this year. I should note that while most of the funded collaborations are with our larger awards, an increasing number of basic biology grants have collaborative funding partners as well. Taking stock of the collaborative projects funded to date, over $148 million contributed to that work has come from the collaborative funding partners themselves. As we see it, there are a host of benefits that arise from these collaborative efforts. First, scientists can work with their most advanced peers from around the world, mitigating the requirement that all funded work must take place in CA, USA. Second, it allows researchers to take advantage of discoveries from other jurisdictions, eliminating the need to ‘reinvent the wheel.’ This advantage directly results in the acceleration of inventions and discoveries. Third, it promotes the efficient use of resources such as shared cell lines, shared assays, shared research equipment, shared data sets, etc. Fourth, in a goal explicitly set forth by Proposition 71, it leads to leveraging funds from multiple 72
jurisdictions to conduct critical research. It allows CIRM and its counter parties to share the cost/burden of their respective research contributions. Fifth, it supports scientists in nascent or early-stage research communities to work with scientists in more advanced arenas, accelerating their progress. Sixth, it facilitates the convergence of ethical and regulatory standards in the field. Finally, it promotes ‘best practices’ among funders, allowing funders to understand shared priorities and to minimize duplicative expenditures.
“
…we believe that collaboration on all fronts is a good thing. We will continue to emphasize this approach and expect the citizens of California and the world to reap the benefits for many years to come.
”
Having said all of the above, a number of questions remain. Will collaborative funding ultimately yield ‘better’ science? Is there enough experience in the stem cell field to support that conclusion? What is the best way to measure? Would the field achieve the same ultimate results without collaborative teams? Does the availability of collaborative funding skew the research that gets pursued? Finally, can regulatory inconsistencies be effectively managed? What happens when regulatory requirements diverge or conflict? Will these inconsistencies ultimately doom the effort? These and other questions will play out over time. Before concluding, I wanted to make a few specific points on the increasing need for collaboration between academia and industry. Through funding provided by Proposition 71, CIRM has the privilege of funding research normally stalled in the so-called ‘Valley of Death’ – that unfunded stage of the research continuum between basic science and Regen. Med. (2012) 7(6 Suppl.)
early-stage clinical trials. A big issue with all of these awards (be they to academics or biotechnology companies) is how will the work in question be funded down the line when our (or other early-stage) money has been spent? This is a pressing problem as the later stage funders (venture capital, big pharma) are not typically getting into the game these days till a funded project has produced Phase II results. To ultimately succeed, our projects need a seamless transition to later stage funding. We spend a lot of time pondering this need and have begun a series of dialogues with big pharma with the goal of driving earlier stage strategic alliances between big pharma and our awardees. Such collaboration benefits both big pharma, which gets an early stage look at potential products to fill their pipeline, and early researchers, who get relationships with deep pockets that can ultimately fund the commercialization of their products should things play out through the early clinical trial process. A classic win-win, if you will. We believe that this approach is going to pay dividends. As of press time, a number of these potential alliances are under discussion. We will continue to facilitate these discussions and are hopeful that a number of these relationships will bear fruit. In conclusion, we believe that collaboration on all fronts is a good thing. We will continue to emphasize this approach and expect the citizens of California and the world to reap the benefits for many years to come.
Financial & competing interests disclosure The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
future science group
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INDUSTRY, COMMERCIALIZATION & COLLABORATION
Organization profile The International Translational Regenerative Medicine Center Mardi de Veuve Alexis*, Karl-Henrik Grinnemo & Richard Jove The International Translational Regenerative Medicine Center, an organizing sponsor of the World Stem Cell Summit 2012, is a global initiative established in 2011 by founding partners Karolinska Institutet (Stockholm, Sweden) and Beckman Research Institute at City of Hope (CA, USA) with a mission to facilitate the acceleration of translational research and medicine on a global scale. Karolinska Institutet, home of the Nobel Prize in Medicine or Physiology, is one of the most prestigious medical research institutions in the world. The Beckman Research Institute/City of Hope is ranked among the leading NIH-designated comprehensive cancer research and treatment institutions in the USA, has the largest academic GMP facility and advanced drug discovery capability, and is a pioneer in diabetes research and treatment. The International Translational Regenerative Medicine Center (ITRC; pronounced ‘i-track’) responds to a major paradigm shift in scientific research and translational medicine that has evolved in recent years with the promise of stem cell research, personalized medicine and innovative therapeutic models that target globally pervasive chronic and life-threatening diseases. The ITRC fills an unmet need to develop a global model that raises the bar on international standards of excellence in biomedical research and coalesces international academic centers of excellence, talented scientists and physicians, and innovative industry leaders toward a common driving goal to move scientific discovery to clinical application. As the world faces enormous health challenges in the 21st century that are compounded by an unprecedented aging population, the ITRC addresses a growing urgency to expedite the pace of translational research to the point of patient care. The ITRC’s principal translational focus is on stem cell technology and innovative regenerative clinical
applications, including molecularbased therapies and biologics that target devastating and debilitating diseases, such as cancer, diabetes and neurodegenerative disorders. Unique from, yet complementary to, numerous biomedical consortia that have been initiated in recent years, the ITRC model is project-based, providing an international hub and infrastructure to support, coalesce and build a network of prominent scientists and clinicians from distinguished research institutions and teaching hospitals worldwide. This project-based approach promotes accessibility, technology exchange and collaboration, and mutually derived discoveries and knowledge that lead to better treatments and cures of major diseases. ITRC has begun to develop and exemplify the highest standards of ethical and clinical protocols in research and clinical applications by facilitating the coordination of research within and among the research groups in each of four regenerative networks at Karolinska Institutet (KI), between the research groups at Beckman Research Institute
Karl-Henrik Grinnemo, Karolinska Institutet, Clinical Research and Regenerative Medicine, Stockholm, Sweden Richard Jove, Beckman Research Institute at City of Hope, Molecular Medicine and Translational Science, Duarte, CA, USA *Author for correspondence: Mardi de Veuve Alexis, International Translational Regenerative Medicine Center, Beckman Research Institute at City of Hope, CA, USA
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at City of Hope (BRI/COH) and among future collaborators and partners (Box 1). Partner institutions maintain their autonomy and uniqueness while benefiting from the resources and synergy provided by the ITRC.
“
The International Translational Regenerative Medicine Center’s principal translational focus is on stem cell technology and innovative regenerative clinical applications…
”
The ITRC platform features state-ofthe-art GMP facilities, centers for stem cell and regenerative medicine, animal research facilities, innovative therapeutics development and human clinical trials. ITRC also facilitates technical assistance between and among partnering institutions and government entities.
Key elements Information exchange Translational science is driving a growing need to share information and databases, including stem cell lines for research, intellectual property rights, databases and other registries. In a world of rapid communication through the Internet and
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The International Translational Regenerative Medicine Center
Box 1. The science: pilot projects. The initial research project areas underway between Karolinska Institutet and Beckman Research Institute at City of Hope and other institutional collaborators include: Parkinson’s and human embryonic stem cell-derived midbrain dopamine neurons Cardiomyocytes and cardiac progenitor cells as strategies for regeneration Leukemia stem cells to evaluate sirtuin inhibitors Targeting proliferating cell nuclear antigen in cancer cells Treating myeloma with natural killer cells and small molecules Early xeno-free clinical-grade human embryonic stem cell lines Project abstracts are available upon request or at www.ITRCmed.net The ITRC’s homepage at ITRCmed.net will present regular news and information complemented by traditional print communications for partners, collaborators and interested consumers, including international research institutions and potential partners, outside principal investigators, media, philanthropic resources and government agencies.
advanced communication technologies that facilitate the exchange of information, universally accessible bioinformatics is also accommodated through the ITRC. Collaboration & enabling technologies The ITRC provides the framework for multidisciplinary collaboration among investigators to efficiently hasten the translation of research findings in basic research to medical practice for improved treatment protocols and health outcomes. Technologies and tools that enable research to clinical practice with GMP, regulatory support resources, and business expertise leading to increased research productivity and commercialization will be developed and shared through the ITRC infrastructure. Government regulatory & research funding support The ITRC offers technical support to help partnering institutions through the process of government approvals. Opportunities to secure funding and grants through both governmental institutions or through private sources in the USA, EU, Sweden and other countries will also be facilitated through the ITRC infrastructure. The ITRC provides partnering institutions a network of expertise to facilitate and complement collaboration among leading researchers (e.g., the formation of disease-focused research teams) to strengthen the potential for funding. Partnering institutions
Partnering institutions shall be defined, future science group
identified and invited to join ITRC on the basis of their internationally recognized expertise and leadership in the field of translational and regenerative medicine. These partnering institutions will be held to strict standards of excellence and core ethical values that define and brand ITRC. In particular, the ITRC draws upon specific expertise and knowledge of leading researchers and clinicians. Through its interactive network, the ITRC facilitates dialogue, joint research initiatives, grant opportunities and clinical trials to develop state-of-the-art treatments, potential cures and a better quality of life for patients suffering with globally pervasive debilitating diseases. The ITRC addresses diseases such as cancer, diabetes and metabolic disorders, neurodegenerative and heart disease through human trials utilizing stem cell technology and transplantation, molecular diagnostics and treatments, and nanotechnology. Partnerships with industry, including pharmaceutical and biotechnology companies, will support commercialization.
which has scientific, administrative and fiduciary oversight, prioritizes research collaborations, evaluates and determines new international, academic and industry partners, and engages in problem-solving on ITRC-related issues. The Operations Team oversees GMP, MTA, technology transfer, regulatory and legal issues, compliance, audits and government grants. A distinguished Advisory Board comprises prominent local and international leaders, patient advocates, researchers from the various KI/BRI-COH regenerative networks and relevant research departments of both founding institutions and future partners. Working Task Forces are integral for each project to facilitate collaboration among principal investigators and others within the scope of specific project goals and objectives. Most of the scientific and clinical research will occur among members of each respective Task Force. Meetings and symposia alternating between KI in Sweden and BRI/ COH in California are held quarterly and biannually to present ITRC projects and research outcomes.
The ITRC is administered from both KI and BRI/COH, respectively and collectively, providing coordination, program execution, management and interface between and among partnering institutions and collaborators; overseeing ITRC budget and operations; coordination of research activities, meeting agendas and symposia; and program delivery among partners and collaborators. KI and BRI/COH oversee and facilitate project funding opportunities and management through the ITRC’s Executive Council,
Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
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ADVOCACY & EDUCATION
Article type
POLICY, REGULATION & ETHICS
CommentarIEs Regulation, manufacturing and building industry consensus Robert Deans Alliances, collaborations and consortia: the International Stem Cell Forum and its role in shaping global governance and policy Rosario Isasi Cell standardization: purity and potency Belinda J Wagner
Opinions Autologous cell therapies: challenges in US FDA regulation Todd N McAllister, David Audley & Nicolas L’Heureux Autologous cell therapies: the importance of regulatory oversight Michael Werner, Tim Mayleben & Gil Van Bokkelen
Perspective Pay-to-participate funding schemes in human cell and tissue clinical studies Douglas Sipp 10.2217/RME.XX.XX © 2011 Future Medicine Ltd
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Commentary Regulation, manufacturing and building industry consensus Robert Deans* As has been true with many emerging technologies, successful clinical development and recruitment of capital sufficient to reach market approval is measured as an industry platform. Risk, failure and achievement by individual companies are shared by all in the context of access to enthusiastic capital markets and codevelopment partnerships. Parallels are often drawn between regenerative medicine technologies and the adoption of antibody biologics, with initial cycles of optimism leading to a financial ‘valley of death’ before validated technologies reach the market and establish the manufacturing and business models sufficient to derisk investment and grow the market opportunity. While this may offer some solace, it behooves us as an industry to challenge the complexities of cell-based therapy and act strategically to build and communicate solutions to those stakeholders on the commercialization path: the translational physicians, regulatory bodies, therapeutic manu facturers, pharma and the capital markers, and finally patient advocacy groups.
healthcare sector waiting on the sidelines for proof of clinical concept was that these emerging technologies did not benefit from experienced development eyes. Critical thinking towards manufacturing scalability and costs has come late into this industry and has become a critical validation and competitive technology fulcrum.
Cell therapeutics for regenerative medicine were in their infancy 15 years ago, and investment milestones were driven by core manufacturing and preclinical data leading to Phase I clinical entry. Investors were not in a financial cycle linked to product approval and sales, but cycling out following these early value creation milestones. As a consequence, many of the critical development criteria such as scalability, cost of goods sold (COGS) and reimbursement price points were only superficially addressed. A consequence of the pharma and
It is important to realize that the business models developed in this paradigm did not capitalize on intellectual property around cell composition of matter, but were tool and service driven. Hematopoietic and blood cells were generally not expanded prior to therapeutic use, and certainly not used outside of autologous or patient-matching restrictions. This industry was regulated through medical devices and reagent CE marking rather than clinical development towards Biologics License Approval approval
Development principles driven by hematopoietic therapies Regenerative medicine cell therapies were birthed from the hematopoietic stem cell transplant space, driven by refinement of stem cell isolation and characterization technology and practiced in a tissue transplant paradigm.
*Author for correspondence: Robert Deans, Athersys Inc., 3201 Carnegie Avenue, Cleveland, OH 44115-2634, USA
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using staged clinical trials. In fact, only in the past year has the US FDA acted to have cord blood products regulated under the Investigational New Drug Application, held by clinical product distributors [101] . Practicing this transplant business model had important ramifications for product acceptance into standard of care. The ‘product’ was in fact a process centered around individual donor tissues and cell processing technology. The practicing physician, in conjunction with hematology societies, was able to run comparative clinical studies between competing technology approaches with public dissemination of product quality and patient response. In fact this open development practice led to effective therapies becoming standard of care in the transplant setting. Physician networks were able to coordinate best practices and accreditation standards through organizations such as International Society Hematology and Graft Engineering (see Table 1), which evolved to the International Society for Stem Cell Therapy (ISCT) and creation of the Foundation for the Accreditation of Cell Therapy. Accreditation standards and harmonized product characterization standards were developed in conjunction with industry and provided the clinician with greater confidence in product conformation.
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The sea change with mesenchymal stromal cells The regenerative medicine landscape has been changed significantly by scientific advances in stem and progenitor cell technologies. Notably, the development of mesenchymal stromal cell (MSC) technologies in the mid-1990s was the first foray for the Investigational New Drug Applicationdriven nonblood cell therapeutics, and also represented a product class defined by cellular composition of matter. As a consequence, a close relationship was created between industry and the FDA and European Regulatory agencies to cross-educate and develop a template for regulating this class of cells. A consensus was developed and harmonized for MSC lot release criteria targeting: Sterility; Identit y, purit y and viabilit y determined by flow cytometry; Cytogenetic stability; Biological potency. Standards for phenotypic markers and biological potency were reinforced by society position papers crafted by academic and industry thought leaders [1,2] , with ISCT playing a major role at early stages. Manufacturing considerations and preclinical development guidelines have become routinized with formal Code of Federal Regulation and informal Regulatory agency policy available as information documents. MSC technologies have had profound influence on the regenerative medicine market based upon key biological properties. First, the low immunogenicity and active immunodulatory properties of this class of cells created a new paradigm for clinical practice, shifting from a patient-designated transplant product to a universal donor product that could be manufactured and distributed as a biologic without patient matching. Second, the ex vivo expansion potential of this class of cells created future science group
Table 1. Cell therapy and regenerative medicine organizations. Acronym
Society
Ref.
AAT
Alliance for Advanced Therapeutics
[102]
ARM
Alliance for Regenerative Medicine
[102]
EPSRC
Engineering and Physical Sciences Research Council
[103]
FACT
Foundation for the Accreditation of Cell Therapy
[104]
ISCT
International Society for Cell Therapy
[105]
ISHAGE
International Society Hematology and Graft Engineering
LRMN
London Regenerative Medicine Network
[106]
SBE
Society for Biological Engineering
[107]
a scalable manufacturing model with many attractive features. The initial practice for MSC therapy was carried out in institutional stem cell processing labs, using T flasks and labor-intensive procedures. With industry engagement in this space manufacturing concepts evolved. Driven initially by Osiris Therapeutics and an effective partnership with Lonza (previously Cambrex), dedicated manufacturing capacity was built around closed 2D minibioreactors exemplified by Corning Life Sciences ten-layer cell factories. Demonstration for manufacturing scale to meet mid- and late-phase clinical testing was a key advance for the industry, and had indirect benefits as well. The combination of universal donor properties and scalable manufacturing reinforced the biologics paradigm for this class of cells, and fostered important codevelopment partnerships based on this model being familiar to pharma and healthcare providers. Initiated by the Osiris/Genzyme partnership, significant capital has come into this space exampled by the Athersys/Pfizer relationship, the Pluristem/United Therapeutics deal, and culminating in extensive capitalization with the Mesoblast/Teva agreement.
Maturing manufacturing in the MSC sector The development path for this class of products has been rocky, based upon less than expected clinical outcomes in the first generation of mid- to latewww.futuremedicine.com
Transitioned to ISCT and FACT
phase clinical studies. However, proof of biological mechanism seems to be generally accepted, and sufficient capital is in play that the MSC industry is now turning to face important questions around COGS and reimbursement. One interesting facet integral to reimbursement discussion is the use of a common therapeutic product to treat a variety of indications. Clinical indications range from life-sparing treatment of graft versus disease, or acute myocardial infarct to chronic inflammation such as inflammatory bowel disease or orthopedics and wound healing. In these cases a different quality impact exists against a pre-existing standard of care associated with coded treatment costs. Reimbursement decisions for a common product with multiple utilities are more likely to be driven by COGS than qualityof-life assessment, a decision with striking implications for company assessment of lead indication and market breadth. The hesitancy in MSC clinical development has had impact on implementation of next-generation manufacturing technologies. The bioprocessing industry has not aggressively entered the scaled cell manufacturing space due to uncertainty for clinical proof of concept and the absence of product approval and validation of economic business models. As a consequence, most therapeutic manufacturers have stayed in a primarily 2D manufacturing mode with limited output in clinical production campaigns. 79
Deans Figure 1. Large-scale evaluation of volume reduction using 50 billion cells costs US$750,000.
Current top-end capacity in practice now yields approximately 1–5 billion cells. Next-generation manufacturing platform targets would increase production campaigns approximately tenfold, and are achieved by increasing the 2D footprint for production using larger cell factories or HYPERstacks® (Corning Life Sciences), with concomitant requirements for robotic and mechanical tools for manipulation. However, these technologies are not significantly reducing COGS and have other associated disadvantages, primarily the absence of downstream cell collection and formulation capacity. The bioprocessing industry has developed tools for downstream processing and large-scale volume reduction, but with focus on collecting biologics rather than cell products. Cell collection technologies are only in their infancy without adoption and implementation in clinical testing. Adaptations of tangential flow filtration (Pall, Millipore) are in development. Scaled cell elutriation (Elutra; Terumo BCT) and counter flow centrifugation (kSep; Invetech) are very promising approaches with cell processing history in the blood cell industry, and it is likely that platforms in this class can successfully meet near-term bioprocessing needs. Gaps also exist in efficient product fill and storage alternatives for scaled manufacturing. Automated product fill bioprocessing tools developed for biologics are not suited for particles such as cells that settle significantly on a fill line, resulting in inconsistent vialing. While the industry is moving towards product fill in cryovials and away from bags, insufficient stability experience has been gained for full validation. Current controlled rate freezers were developed to process blood cell bags or vials at small scale, and development and validation of large-scale freezing platforms and inventory storage devices are key. These technology gaps exist as a consequence of unproven market potential. 80
Recruitment of the bioprocessing sector into this space can be influenced by the community effort of therapeutic manufacturers and their societies. There are recent examples for cooperative crosstalk and encouraging signs for change. The Society for Biological Engineering has integrated manufacturing aspects of cell therapeutics into their focus. Organizations like Bioprocessing International have aligned with ISCT and Alliance for Regenerative Medicine (ARM) for crosscommunication of clinical development progress and manufacturing perspectives to provide the bioprocessing industry with an assessment of growth opportunity and encouragement to develop products in this space. Strong lobbying and education influence is being driven by societies such as ARM and ISCT.
How can community efforts solve manufacturing roadblocks? Academic and industry groups are now evaluating new thinking in manufacturing platforms for MSC and related products. Much effort is going into evaluation of hollow fiber bioreactors, clearly scalable given their use in the vaccine and gene therapy industry, as well as growth of cells on microcarriers suitable for use in stirred tank or packed bed bioreactors. This is a daunting target to reach for, however, due to extensive development costs. The development costs associated with performing large-scale cell expansion and downstream processing development may be prohibitive against current available market capital. With current industry standards for MSC production averaging US$15 per million cells, a large-scale evaluation of volume reduction using 50 billion cells poses a $750,000 cost (Figure 1). With many undetermined variables this is prohibitive for the bioprocessor and prohibitive for the therapeutic company. Regen. Med. (2012) 7(6 Suppl.)
Industry initiatives are now proceeding to form consortia for solving downstream processing requirements common to all therapeutic manufacturers, which is a wise decision. Progressive academic centers with strengths in bioengineering and bioprocessing, such as UC Davis and the University of Loughborough, are logical neutral testing centers for public domain process improvements. In addition, the last few years have shown strengthened cooperative initiatives and evolution of industry segments within regenerative medicine societies, the most notable being the Industry Community of ISCT and the future science group
Regulation, manufacturing & building industry consensus
momentum established by ARM. The first collaborative publication by these members is in press in Cytotherapy on the subject of potency assays, and a second generation of initiatives on potency and cell characterization are coming forward. Most importantly, these societies are striving to have an international voice. The Alliance for Advanced Therapies has been launched as a sister organization for ARM, and ISCT has placed global outreach as a high priority in its strategic initiatives.
What is the future? Ironically, while the universal donor concept around MSC has done so much to foster business models and solicit capital investment in the regenerative medicine space, the development of technologies to utilize or create pluripotent stem cell biology is crafting yet another paradigm, that of personalized medicine. It is not difficult to forecast that postnatal tissues will be collected at birth, with genome sequencing determining predisposition for disease. Preparation for this is actually building within the bioprocessing industry, with evolution of disposable bioreactors suitable for producing limited clinical product designated for an individual.
Interestingly, this evolution is also riding on the wave of MSC therapies, with devices such as the Quantum® (Terumo BCT) and the Xpansion™ (ATMI) serving this purpose. The regulatory environment in Europe is more supportive of investigatorbased initiatives for patient designated manufacturing with an evolving position on hospital exemptions as an allowance for autologous product manufacturing within the patient treatment clinical center.
Open code development principles Perhaps the most important principle facing the regenerative industry is the promotion of open code development principles. This has several dimensions – several organizations have worked extensively to structure workshops and publish standards for preclinical models and clinical end points and trial design, spanning stroke [3] , solid organ transplant [4] and peripheral vascular disease [5] . These organizations have invited and exposed regulatory agencies to these workshops for the purpose of crafting testing standards to support success in these sectors for all. More importantly is the willingness of industry to contribute clinical data for product classes to clinical data registries. As mentioned above, the hematopoietic
transplant community was able to work with open disclosure around performance of tools and reagents for hematopoietic stem cell transplantation prior to product approval. With MSC as a case study, this is not the case. Bake-off clinical studies are not currently required by the FDA and others, and it is not clear if and when products within a class will be required to demonstrate superiority as a requirement for approval. We are unfortunately a good distance away from alternate MSC products carrying a label like a can of soup describing effective potency. Hopefully, we can look beyond short-term competitive instincts and understand the value of building an industry segment emphasizing the patient and able to compete in new world pharmacoeconomic order.
Financial & competing interests disclosure The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
References 1
2
3
Dominici M, LeBlanc K, Mueller I et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 9, 301–302 (2007).
4
Horwitz E, Le Blanc K, Dominici M et al. Clarification of the nomenclature for MSC: The International Society for Cellular Therapy position statement. Cytotherapy 8, 315–317 (2005).
5
Stem Cell Therapies as an Emerging Paradigm in Stroke Participants. Stem Cell Therapies as an Emerging Paradigm in Stroke (STEPS): bridging basic and clinical science for cellular and neurogenic factor therapy in treating stroke. Stroke 40(2), 5102515 (2009).
Websites
future science group
Dahlke M, Hoogduijn M, Eggenhofer E et al. Towards MSC in solid organ transplant: 2008 position paper of the MISOT study group. Transplantation 88(5), 614–619 (2009).
102 Alliance for Regenerative Medicine.
Sherman W, Mazouz C, Deans R, Patel A. Commercialization of trials for peripheral arterial disease. Cytotherapy 13(10), 1157–1161 (2011).
104 Foundation for the Accreditation of
101 FDA update on cord blood regulation: new
guidance. www.fda.gov/downloads/ BiologicsBloodVaccines/NewsEvents/ WorkshopsMeetingsConferences/ UCM200358.ppt
www.futuremedicine.com
www.alliancerm.org/ 103 Engineering and Physical Sciences
Research Council. www.epsrc.ac.uk/Pages/default.aspx Cellular Therapy. www.factwebsite.org/ 105 International Society for Cellular Therapy.
www.celltherapysociety.org/ 106 London Regenerative Medicine Network.
www.lrmn.com/ 107 Society for Biological Engineers.
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POLICY, REGULATION & ETHICS
Commentary Alliances, collaborations and consortia: the International Stem Cell Forum and its role in shaping global governance and policy Rosario Isasi* It can be asserted that the stem cell field be classified as a global enterprise [1] , as evidenced by the proliferation of transnational stem cell initiatives, alliances, networks and institutions. Moreover, the sustainability of the field is – to a great extent – dependent on the ability of such actors to enable cross-jurisdictional collaboration by fostering the sharing of stem cell-related resources and data [1]. Kofi Annan’s statement that “arguing against globalization is like arguing against the law of gravity” [101] could not be more true when applied to the context of stem cells. Efforts directed at addressing the challenges posed by globalization are flourishing, particularly with respect to the ongoing need for governance and policy interoperability. While heterogeneity of national policies governing stem cell research at all its stages (collection, derivation, use, storage and distribution) still remain within and between jurisdictions, the globalization of the stem cell field has, somewhat paradoxically, contributed to the convergence of normative and scientific standards, as well as governance and ethical principles (Figure 1) [1] . As a vast range of pluripotent stem cell lines are continuously immortalized, transformed and distributed across jurisdictions; so are policy goals, models and mechanisms for implementation, which are mobilized across the globe in space and time [2] by the work of scientific alliances, networks and other institutions. This article provides a succinct review of the International Stem Cell Forum (ISCF), the first transjurisdictional organization of funders of stem cell research [102] . It examines three ISCF
initiatives as examples of how international consortia can help shape global governance and scientific practice.
Alliances, collaborations & consortia & the shaping of global governance and policy Policy transfer is conducted by a range of national, international and regional actors in a multidisciplinary and multidimensional manner [3,4] . Notable examples are: the International Society for Stem Cell Research (ISSCR) [103] , the ISCF [102] together with the International Consortium of Stem Cell Networks [5] , as well as the Inter-State Alliance on Stem Cell Research [6] , the EU [104] and finally, the Organization for Economic Co-operation and Development [105] . By asserting legitimacy pressures, these ‘policy agents’ serve as mediators of crossjurisdictional policy transfer and innovation by promoting transnational governance [4] while simultaneously urging jurisdictions to engage in normative action. The power of these institutions in fostering scientific progress by promoting best practices and policy
*Author for correspondence: Rosario Isasi, Centre of Genomics and Policy, Faculty of Medicine, Department of Human Genetics, McGill University area and Génome Québec Innovation Centre, 740 Dr Penfield, Suite 5206, International Stem Cell Forum: Ethics Working Party area; rosario.isasi@mcgill.ca
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innovation should not be underestimated. Given that socio–cultural, historical and political contexts greatly shape both the debates and policy outcomes, best practices developed by these actors are also promoting prospective policy evaluation, as they in turn build on the knowledge and experience of other institutions and jurisdictions in developing and implementing policy frameworks [7] . Professional organizations, such as the ISSCR [103] , provide an institutional foundation for the development and dissemination of best practices. ISSCR has been fostering global governance and international cooperation in stem cell research and clinical translation since its inception [106] through the adoption of guidelines seeking to promote responsible, transparent and uniform practices worldwide [107] . Furthermore, a global governance and educational tool was promoted with ISSCR’s initiative ‘A Closer Look at Stem Cell Treatments’ [105] , which targeted the complex problem of unproven stem cell interventions marketed around the world (‘stem cell tourism’). Additionally, a global, prospective and ethical framework has also been promoted by the Canadian Stem Cell Foundation, which in 2009 launched the ‘Stem Cell
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Peru
Panama
USA
Canada
Colombia
Argentina
Brazil
South Africa
Estonia Latvia Lithuania
Finland
Israel
Tunisia
Malta
India
Greece
Thailand
Vietnam
Japan
Australia
New Zealand
Philippines
Taiwan
South Korea
Singapore
China
Cyprus
UK Neth. Germany Poland Belgium Cz. Rep. Lux. Austria Slovakia France Switz. Hungary Slovenia Romania Georgia Bulgaria Italy Portugal Spain Turkey Ireland
Denmark
Norway
Sweden
Figure 1. Current laws and policy approach on stem cell research globally. hESC: Human embryonic stem cell; IVF: In vitro fertilization; SCNT: Somatic cell nuclear transfer. Redrawn from [111].
Iceland
Federated country where hESC and derivation are both a matter of federal and state law. Policy approaches range from permissive to restrictive
No specific legislation in place regarding embryo or hESC research
Restrictive approach (prohibitions on embryo research or on derivation and use of hESC embryos, or research limited to imported hESC lines)
Intermediate approach (restrictions in place fo hESC research and derivation)
Permissive approach with respect to hESC research derivations (IVF, SCNT)
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Charter’ [8] . Founded on the values guiding the protection of human rights, the Charter articulates five principles advocating responsible stem cell science. These principles are: Responsibility to maintain the highest level of scientific quality, safety and ethical probity; Protection of citizens from harm and the safeguarding of the public trust and values; Intellectual Freedom to exchange ideas in the spirit of international collaboration; Transparency through the disclosure of results and of possible conflicts of interest; Integrity in the promotion and advancement of stem cell research and therapy for the betterment of the welfare of all human beings. International cooperation and transnational education are also the remit of the International Consortium of Stem Cell Networks [5] . Their innovative approach seeks to expand “the concept of national research networks to the international level” with a series of knowledge transfer activities fostering the exchange of best practices [5] . As with other actors, professional organizations employ the power of persuasion as their main tool with regards to policy transfer, given that their authority for enforcement and accountability, including their capacity to impose sanctions, is virtually absent. In fact, despite the globalization phenomena, governance remains almost entirely the role of national authorities [9] . Funding organizations have an essential role to play in fostering international cooperation and promoting scientific integrity while accelerating scientific progress.
improving scientific knowledge, as well as the ability to prevent and treat disease, the realization that this could only be achieved through the promotion of international collaboration and funding support led to the launch of the ISCF [102] . The ISCF was established in 2003 under the auspices of the UK Medical Research Council, and was comprised of 21 funding organizations of stem cell research around the world, with the overall objective to promote global good practice. Areas identified by ISCF members where joint work would be particularly beneficial: Encouraging collaborative research across nations, boundaries and disciplines; Promoting sharing of resources and data, including cell lines, scientific protocols and guidance documents; Fostering training for researchers worldwide in the handling, growing and expansion of human stem cell lines; Identifying key research gaps and addressing them by capitalizing on national strengths; Facilitating transnational collaborations via funding schemes; Considering issues relating to the management of intellectual property in stem cell research and development; Analyzing ethical issues in stem cell research. To achieve its objectives the ISCF supports three major international initiatives.
The ISCF Ethics Working Party (EWP) is an independent body mandated to review fundamental ethical policies pertaining to stem cell research. The EWP recognizes the complexities of the stem cell field, which is characterized by a vast range of pluripotent stem cell research and potential therapies, which are performed in a context of political and cultural diversity [108] . The ISCF-EWP aims to identify the different national ethical–legal and policy landscapes [10] , in order to facilitate international dialogue on fundamental ethical issues, and to foster shared ethical principles so as to guide the conduct of stem cell research and policy making. As the ISCF-EWP fulfills this mission, via monitoring, horizon scanning and analyzing ethical issues and policy frameworks regarding stem cell research and stem cell-based therapies, the EWP continues to prospectively identify issues that are in need of ethical deliberation and further policy guidance. The ISCF-EWP work program is designed to be prospective and responsive to the dynamic nature of policy and regulatory environments, as well as the rapid pace of scientific developments. As such, it has focused on analyzing substantive requirements and procedural safeguards in the regulation of stem cell research [11] , the use of monetary payments for the procurement of oocytes for stem cell research [12] , as well as ethical and regulatory issues surrounding stem cell banking [13] . Moreover, the EWP’s seminal policy statements on the managing of genetic data [14] and the disclosure research results and incidental findings in the context of stem cell research and banking [15] continues to inform scientific practice.
Box 1. The International Stem Cell Forum key principles. The International Stem Cell Forum members have agreed a set of key principles that determine their approach to stem cell research. They are: Opposition to human reproductive cloning
The ISCF Once it was established that the true potential of stem cell research was 86
Use of adult somatic human stem cells, as well as embryonic human stem cells The generation of embryonic human stem cell lines should be minimized International harmonization of ethical and intellectual property rights Regen. Med. (2012) 7(6 Suppl.)
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International Stem Cell Forum & its role in shaping global governance & policy
The International Stem Cell Banking Initiative (ISCBI) has been established with the vision of creating a global, interoperable network of stem cell banks, working jointly towards indentifying and harmonizing best practices for banking, characterization and testing of pluripotent stem cell lines [16] . ISCBI’s vision and mission is “to create a solid scientific and ethical framework for international stem cell banking and research” [17] . Important harmonization and standardization work has been carried out by ISCBI. In 2008, ISCBI adopted its first best practices: the ‘Consensus Guidance for Banking and Supply of Human Embryonic Stem Cell Lines for Research Purposes’ [18] . This guidance document seeks to be comprehensive in managing a wide range of aspects involved in a bio resource: from procurement to ethical provenance, governance, banking procedures, quality control, safety testing and international distribution. A set of best practices for clinical-grade pluripotent stem cell lines is currently being developed by ISCBI. The new guidelines will establish an international set of standards for stem cell lines destined to be used in clinical translation as well as clinical trials, and will cover procurement, characterization, testing, maintenance and shipment. It is envisaged that ISCBI will have an important role to play in shaping research and its clinical translation by creating the foundations for stem cell banking [17] .
The International Stem Cell Initiative (ISCI) recognizes the importance of scientific consortia in high-quality scientific practice by promoting standardization. The ISCI was created in 2004 with the view of establishing criteria and techniques to support the development and use of human embryonic stem cell lines for medical applications [19] . ISCI groundwork is divided into three initiatives: the ISCI-1 main objective was to systematically define key features of human embryonic stem cells (hESCs) and to establish whether or not hESCs share common features. The ISCI-1 enlisted the work of 17 laboratories (spanning 11 different countries) to analyze 59 independent hESCs and established a globally agreed upon set of criteria for characterizing stem cell lines [20] . ISCI-1 identified “a set of standard markers that could be used to characterize and monitor the behavior of hESCs in future experiments” [109] and established the ISCI Registry [110] , which published the results of the work carried out by ISCI projects. This was followed by ISCI-2, which was charged to compare the performance of different media for the culture of hESCs and to study the genetic changes that can occur in hESCs on prolonged passages in culture [21] . Finally, ISCI-3 is entrusted to establish a consensus on quantifiable protocols that can be used to assess the capacity of individual pluripotent stem cell lines (ES or iPS) to differentiate along specific lineages [22] .
Conclusion Foresight and global approach to scientific innovation are two characteristics of major national and transnational stem cell initiatives, alliances, networks and institutions. Indeed, the ‘globalization’ of the stem cell field has shifted the sphere of debate and action from national to the international [23] . Despite the strengthening of international consortia seeking to accelerate scientific progress by promoting collaboration via the sharing of resources and the establishment of best practices, an effective global governance framework is yet to be consolidated. The latter is reflected in the challenges ensuing from the controversial phenomenon of stem cell tourism [24] . Funding consortia, such as the ISCF, have a major role to play as agents both for policy transfer and global governance. Financial & competing interests disclosure The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
References 1
Isasi R. Policy interoperability in stem cell research: demystifying harmonization. Stem Cell Rev. 5(2), 108–115 (2009).
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Marsden G, Stead D. Policy transfer and learning in the field of transport: a review of concepts and evidence. Transport Policy 18(3), 492–500 (2011).
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Newmark AJ. An integrated approach to policy transfer and diffusion. The review of policy research (summer 2002). Rev. Pol. Res. 19(2), 151–180 (2002). Stone D. Transfer and translation of policy. Policy studies doi:10.1080/01442872.695933 (2012) (Epub ahead of print). Lyall A. The International Consortium of Stem Cell Networks (ICSCN). World Stem
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Cell Report (2010). Genetics Policy Institute, USA, 107–110 (2010). 6
Lomax G, Forsberg EJ, Gincel D et al. Policy harmonization through collaboration: the interstate alliance on stem cell research. World Stem Cell Report (2010). Genetics Policy Institute, USA, 100–103 (2010).
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Randma-Liiv T, Riin Kruusenberg A. Policy transfer in immature policy environments: motives, scope, role models and agents. Public Adm. Dev. 32, 154–166 (2012).
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Knoppers BM, Isasi R, Willemse L. Stem Cell Charter. Regen. Med. 5(1), 5–6 (2010).
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research: substantive requirements and procedural safeguards. Human Reprod. 21(10), 2474–2481 (2006). 10 Isasi RM, Knoppers BM. Mind the gap:
policy approaches to embryonic stem cell and cloning research in 50 countries. Eur. J. Health Law 13(1), 9–25 (2006). 11 International Stem Cell Forum Ethics
Working Party. Ethics issues in stem cell research. Science 312(5772), 366–367 (2006). 12 For the International Stem Cell Forum
Ethics Working Party: Knoppers BM, Revel M, Richardson G et al. Letter to the Editor: oocyte donation for stem cell research. Science 316, 368–369 (2007).
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13 Isasi R, Knoppers BM. Governing stem cell
banks and registries: emerging issues. Stem Cell Res. 3(2–3), 96–105 (2009). 14 Knoppers BM, Isasi R, Benvenisty N et al.
Publishing SNP genotypes of human embryonic stem cell lines: policy statement of the International Stem Cell Forum Ethics Working Party. Stem Cell Rev. 7(3), 482–484 (2011). 15 International Stem Cell Forum Ethics
Working Party. The disclosure and management of research findings in stem cell research and banking Regen. Med. 7(3), 439–448 (2012). 16 Crook JM, Hei D, Stacey G. The
International Stem Cell Banking Initiative (ISCBI): raising standards to bank on. In Vitro Cell. Dev. Biol. Anim. 46(34), 169–172 (2010). 17 Stacey G, Healy L. Banking stem cell lines:
an international perspective. World Stem Cell Report (2010). Genetics Policy Institute, USA, 107–110 (2010).
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Characterization of human embryonic stem cell lines by the International Stem Cell Initiative. Nat. Biotech. 25(7), 803–816 (2007). 21 The International Stem Cell Initiative.
Comparison of defined culture systems for feeder cell free propagation of human embryonic stem cells. In Vitro Cell Dev. Biol. Anim. 46(3–4), 247–258 (2010). 22 The International Stem Cell Initiative.
Screening ethnically diverse human embryonic stem cells identifies a chromosome 20 minimal amplicon conferring growth advantage. Nat. Biotech. 29(12), 1132–1144 (2011). 23 Castells M. The new public sphere: global
civil society, communication networks, and global governance. Ann. Am. Acad. Polit. Soc. Sci. 616(78), 78–93 (2008). 24 Sipp D. Global challenges in stem cell
research and the many roads ahead. Neuron 70(4), 573–576 (2011).
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Consensus guidance for banking and supply of human embryonic stem cell lines for research purposes. Stem Cell Rev. 5(4), 301–314 (2009). 19 Andrews PW. The role of the international
stem cell initiative in facilitating human ES cell research. World Stem Cell Report (2010). Genetics Policy Institute, USA, 118–120 (2010).
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Websites 101 Secretary-General Kofi Annan’s Opening
Address to the Fifty-Third Annual DPI/ NGO Conference. www.un.org/dpi/ngosection/ annualconfs/53/sg-address.html 102 International Stem Cell Forum.
www.stem-cell-forum.net/ISCF
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103 International Society for Stem Cell
Research. www.isscr.org 104 European Union.
http://europa.eu/policies-activities/index_ en.htm 105 Organization for Economic Co-operation
and Development. www.oecd.org/ 106 International Society for Stem Cell
Research (ISSCR). Guidelines for the conduct of human embryonic stem cell research. www.isscr.org/guidelines/ ISSCRhESCguidelines2006.pdf 107 International Society for Stem Cell
Research. Guidelines for the clinical translation of stem cells, 1–19 (2008). www.isscr.org/clinical_trans/pdfs/ ISSCRGLClinicalTrans.pdf 108 International Stem Cell Forum Ethics
Working Party. www.stem-cell-forum.net/ISCF/initiatives/ ethics-working-party 109 International Stem Cell Initiative.
http://stem-cell-forum.net/ISCF/ initiatives/isci/ 110 ICSI Stem Cell Registry.
www.stem-cell-forum.net/ISCF/initiatives/ isci/stem-cell-registry/ 111 Stem cell research world map.
www.stemgen.org/mapworld.cfm
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Commentary
Cell standardization: purity and potency Belinda J Wagner* The regulatory requirement to demonstrate purity and potency presents a much bigger challenge to regenerative medicine compared with small-molecule drugs and protein biologics because of the desire to introduce living cells into the human body. Any cell population is inherently heterogeneous and bioresponsive – characteristics that make standardization by traditional methods extremely difficult. Standardization is on a ‘critical path’ to demonstrating purity and potency as I will discuss. Although difficult, I believe standardization is not impossible. In fact, I believe untapped resources of benefit to the regenerative medicine and cell therapy industries exist, particularly in the area of oncology molecular diagnostics. Leveraging the vast amounts of cellular biomarker data that are linked with clinical outcomes and the established reimbursement strategies generated by oncology product development efforts might accelerate the translation of regenerative medicine products from the bench to the clinics both scientifically and financially. The technical difficulty of establishing purity and potency for a therapeutic using standardized methods increases with the complexity of the therapeutic’s structure and the potential for variability in the processes by which it is manufactured. Both the complexity of therapeutic structure and the potential variability in manufacturing processes have increased dramatically. One can divide this complexity into three major categories (Figure 1). The least complex are small-molecule therapeutics produced by chemical reactions. More complex are biopharmaceuticals (e.g., recombinant human proteins, fusion proteins and monoclonal antibodies), where living organisms (e.g., plant and animal cells, bacteria, viruses or fungi) produce the molecule, which is then purified. The highest complexity is cell-based therapeutics, where viable cells are introduced into a patient, whether as cells alone or as components of a combination product. Another perspective is to look at product characteristics that are relevant for establishing purity and
potency. The final products of both small-molecular therapeutics and biopharmaceuticals are fairly static entities. Environmental conditions can affect them, but the effects are predominantly chemical or conformational. Living cells are another matter entirely – very subtle or dilute environmental cues can trigger cascade effects that change both the intra c ellular and extracellular environments extremely rapidly. Even clonal cells expanded in culture are not identical; they are heterogeneous populations, harboring differences that change over time. Depending on when a sample is taken, aliquots of living cell populations can have different percentages of cells at each phase of the growth cycle, signaling pathways can have different sensitivities and so on. Getting reproducible results from separate in vitro experiments often requires extremely tight control of both timing of process steps and reagents. Human bodies, particularly human bodies that harbor disease conditions that can take decades to establish, are not so well-controlled.
*Author for correspondence: Belinda J Wagner, Biographic Design Consulting, Winston-Salem, NC, USA; phdnofuddy@yahoo.com
10.2217/RME.12.69 © 2012 Future Medicine Ltd
Both the population and bioresponsiveness characteristics of cells are a double-edged sword. On the one hand, by being bioresponsive, cells can respond to the environment into which they are introduced in a more tailored manner. For example, diabetic patients requiring insulin must calculate the correct dose to administer multiple times a day. Insulin pumps have simplified the delivery of a correct dose, but problems with blood sugar management still occur. A cell therapy approach would treat insulin-dependent diabetes with bioresponsive pancreatic b-cells, placing them where they would have access to the same sensing mechanisms as native b-cells would in a nondiabetic patient, to deliver the right amount of insulin to the bloodstream continuously. On the other hand, a small subpopulation of cells within a delivered dose could react to the patient tissue environment in an unanticipated way. For example, certain cytokines can tip the balance between stimulating or suppressing inflammation depending on whether they are present in low or high concentration, or if they are present in certain combinations with other cytokines. A small
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Cell-based therapeutics
Biopharmaceuticals
Small-molecule therapy
Levels of complexity
Figure 1. Complexity of therapeutic structure.
percentage of cells could be primed to trigger an inflammatory cascade, which could then influence the entire dose of cells to respond by stimulating inflammation. Such unanticipated population shifts could trigger an adverse event in a patient. How do we develop cell therapies that reap the benefits of bioresponsiveness and avoid the pitfalls? By adhering to basic principles of standardization, identity, purity and potency in the context of heterogeneous populations of living cells.
Standardization Standards became highly important during the Industrial Revolution with the need to make interchangeable parts. In the life sciences, standards help data become more interchangeable by providing a common comparator for results. A simple illustration of a situation where standardization is lacking in cell therapy product discovery is provided by a widely used procedure to isolate mesenchymal stromal cells 90
(MSC) – applying a cell suspension (e.g., mononuclear cells from bone marrow or the stromal vascular fraction from adipose tissue) to tissue culture plates and expanding the population of cells that adheres to the tissue culture plate surface. Some of the parameters that could vary among preparations are the procedures and reagents used to generate the cell suspension, the surface composition of the tissue culture plates, the media components used to nourish the cells during the adherence phase, the relative proportion of adherent to nonadherent cells and so on. Variation in any one of these parameters can change the overall composition of the resulting ‘MSC’ population, making it almost impossible to compare results obtained with MSC prepared by separate groups, even if those groups isolated cells from different aliquots of the same tissue.
Identity & its relationship to purity & potency Part of the difficulty of comparing results from supposedly related studies (like those evaluating the clinical utility Regen. Med. (2012) 7(6 Suppl.)
of MSC) stems from the relatively limited parameters used to identify cells as MSC. The British Standards Institution Publicly Available Specification 93:2011 defines an identity test as being “capable of distinguishing the cellular active substance from any other cells that might reasonably be present in the cellular starting material or final cell therapy product” (p. 5). Rare is the published study that characterizes the proportion or identity of nontarget cells present in the cellular starting material; more rare are published studies that track the dilution of such potentially undesirable cell types in the final cell therapy product; and even more rare are studies that evaluate whether the presence of cell types that are removed from the cellular starting material are deleterious to the observed in vivo effects of administering the final cell therapy product. The first step toward standardization in cell therapy is establishing a body of published work where each study contains the basics of defining identity tests for targeted and other cell types that meet the threshold defined in British Standards Institution Publicly Available Specification 93:2011 [1] ; measurfuture science group
Cell standardization: purity & potency
ing the proportion of target and other cell types in cellular starting material, intermediate production steps, and final cell therapy product (purity); and establishing whether cells that are removed during production elicit adverse effects in vivo – either alone or in combination with the final cell therapy product (potency). These data can be published in a manner that informs the overall field of cell therapy while maintaining the confidentiality of intellectual property critical for investment (process, composition of matter and so on).
Most promising paths forward Overall, the field of cell therapy still needs to develop further maturity in its understanding of identity before standards for purity and potency can be developed, but are there paths forward that could leverage such understanding that has matured in other fields? I believe so. One of the most promising landscapes that cell therapy could leverage is oncology molecular diagnostics. Like cell therapy products, tumors are a heterogeneous population of cells. Many of the techniques being developed to less invasively sample patients for diagnosis, treatment monitoring, and post-treatment surveillance are geared toward population sampling. Mass spectrometry is being used to establish proteomic profiles and to detect specific peptides that signal beneficial or deleterious expression in blood and tissue samples. RT-PCR-based assays can provide similar surveillance for gene expression. Genetic stability is being monitored at the population level by focusing on shifts in mitochondrial DNA sequences. Microfluidics technologies can sample living cells within closed systems. Multiplexing capabilities are being developed to leverage the advantages of imaging using sample formats that are limited in quantity. Most beneficial to the financial support of cell therapy product development is the linkage of oncology molecfuture science group
ular diagnostics to both the traditional pharma investment paradigms and to validated assay systems that have wellestablished reimbursement pathways. Also beneficial to cell therapy is the fact that many of these data have been assayed in huge numbers of clinical samples (prediagnosis, during treatment, and post-treatment, often for extended timeframes) and the growth of such data is still in log phase. Therefore, it should be possible to assess the background of candidate biomarkers in a variety of target patient populations retrospectively or gather prospective data via IRB-approved protocols in institutions conducting clinical trials. Once biomarkers that are correlated with clinical outcomes are identified through establishing a body of published work connecting the basics of identity and its relationship to purity and potency, standards can be developed that allow comparison of independently produced cell therapy products at different stages of production. Such reference standards allow mechanistic parameters that might account for different clini-
cal outcomes to be measured objectively without divulging intellectual property. One such example, of relevance to cell therapies that use scaffolds, is the reference materials scaffolds being developed by the National Institute of Standards and Technology (NIST) (Figure 2). Developing analogous reference materials for cell therapy biomarkers would not only allow comparison between different cell products, but could serve to measure equivalence between production processes at different sites or at different phases of scale-up. In summary, in order for the cell therapy industry to realize the economic benefits of standardization, more work needs to be accomplished in the foundational concept of identity, particularly in linking identity characteristics of both target cells and discarded cell types to clinically relevant responses. More studies at the earliest phases of product discovery should document not only the presence of the active cellular population, but its proportion in the starting material relative to other cell types and whether the persistence of other cell types or the presence of
Figure 2. Reference material scaffolds. Reference material scaffolds are being developed that can serve as a calibration point for comparing scaffold measurements between different laboratories. The first-generation reference scaffolds have been deployed and focus on scaffold structure and porosity. A second-generation reference scaffold is under developement that will focus on measuring cell response (adhesion and proliferation) to 3D scaffolds. NIST: National Institute of Standards and Technology.
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alternate biological states of the active cellular population elicit deleterious effects in vivo. Leveraging the maturity of standardization that exists in oncology molecular diagnostics might be a promising direction in which the ability to develop standards for cell therapy might be accelerated.
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Financial & competing interests disclosure The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the Âproduction of this manuscript.
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Website 1
British Standards Institution. PAS 93:2011 Characterization of human cells for clinical applications. Department for Business Innovation and Skills, London, UK, 2011. www.bsigroup.com/upload/Standards%20 &%20Publications/PSS/PAS93-2011.pdf (Accessed 10 July 2012).
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POLICY, REGULATION & ETHICS
Opinion
Autologous cell therapies: challenges in US FDA regulation Todd N McAllister*, David Audley & Nicolas L’Heureux Cell-based therapies (CBTs) have been hailed for the last two decades as the next pillar of healthcare, yet the clinical and commercial potential of regenerative medicine has yet to live up to the hype. While recent analysis has suggested that regenerative medicine is maturing into a multibillion dollar industry, examples of clinical and commercial success are still relatively rare [1–3]. With 30 years of laboratory and clinical efforts fueled by countless billions in public and private funding, one must contemplate why CBTs have not made a greater impact. The current regulatory environment, with its zero-risk stance, stymies clinical innovation while fueling a potentially risky medical tourism industry. Here, we highlight the challenges the US FDA faces and present talking points for an improved regulatory framework for autologous CBTs. Clearly the FDA’s risk-averse stance toward the clinical use of high-risk medical technologies has influenced the commercialization of medical innovation. While the USA still plays a prominent role in the discovery phase, today, few technologies are translated to initial clinical use through the US regulatory framework. Most CBTs, like other recent medical innovations (i.e., abdominal aortic aneurysm repair or transcatheter valve devices) are developed through an Asian- or EU-centric pathway. Geron’s recent exit from the field of regenerative medicine after a US-centric strategy is attributed by most observers directly to the FDA’s aggressive stance and protracted pathway to initial human testing [4] . This departure serves as a sad reminder of the negative economic and clinical impact of an ultraconservative approach, and supports such conclusions made elsewhere [5,6] . That said, the FDA is an underfunded and understaffed agency in the unenviable position of trying to regulate the best-funded and most innovative biomedical industry in
the world. No one will argue that it is challenging to produce guidance documents at a rate matching the evolution of CBTs. Moreover, the FDA’s conservative stance is somewhat understandable in light of the unfairly harsh press and political fallout surrounding previous failures (e.g., Vioxx, silicone breast implants) as well as societal and legal trends toward zero-risk [7–9] . This does not, however, justify a regulatory framework that stalls the clinical development of these technologies. While it may be unfair to correlate the slow progression of CBTs solely with an overly exuberant FDA, it is clear that the regulatory framework in the USA has played a prominent role in creating a stem cell ‘tourism’ industry. While it is difficult to accurately assess the size of this market, we estimate that there are approximately 350 stem cell clinics worldwide seeing an average of five tourists per month, giving a total of 21,000 stem cell medical tourists each year out of a total of 3,000,000 medical
*Author for correspondence: Todd N McAllister, Cytograft Tissue Engineering, Inc., 3 Hamilton Landing, Suite 220, Novato, CA 94949, USA David Audley, Cytograft Tissue Engineering, Inc., 3 Hamilton Landing, Suite 220, Novato, CA 94949, USA Nicolas L’Heureux, Cytograft Tissue Engineering, Inc., 3 Hamilton Landing, Suite 220, Novato, CA 94949, USA
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tourists. Through interviews we have estimated that each treatment costs approximately US$25,000 resulting in an annual spend of over US$500 million on unregulated stem cell treatments. This represents approximately 0.7% of the overall medical tourism patient flow and about 3% of the total revenues (assuming total worldwide revenues generated by medical tourism are US$15 billion) [101,102] . It is ironic, then, that at the height of the negative press surrounding stem cell tourism, the FDA is exerting an even greater influence in attempting to redefine CBTs and cracking down on USbased clinics conducting point-of-care treatments under the practice of medicine [10–13] . The most striking of recent events is the dismissal of the lawsuit against the FDA brought by regenerative sciences [14] . This court case, in combination with a lawsuit from Cytori Inc., moves by the Texas Medical Board, and FDA warning letters sent to physicians harvesting stromal vascular fraction, have brought the situation to the forefront of both the scientific and lay press [15,103,104] . Adding to the irony is the fact that some of the most vocal and influential participants in this debate come not from a medical, scientific, or even legal background, but rather, a religious or ethical background [14,16] . It would seem that the availability of adult autologous stem cells should
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be based on rational safety and efficacy arguments, and the debate should be driven by individuals with the training and experience to appropriately evaluate the risk and benefit associated with manufacturing controls or treatment methodology. As we analyze this situation and try to provide improved regulatory paradigms, it is important to objectively recognize the biases, shortcomings and financial incentives held by the various stakeholders. On one end of the spectrum is the academic community. Through societies such as the International Society for Stem Cell Research, this community tends to echo the FDA’s conservative stance, and encourages continued bench-top and animal research. While justified in many cases, we cannot ignore the potential financial self-interest served by this message. That is, the NIHfunded academic community is well served by a regulatory policy that promotes a longer and basic researchintensive developmental path. Indeed it is no surprise to see the International Society for Stem Cell Research closely linked to the war on stem cell clinics [17,105] . With pressures from the NIH roadmap to focus on translational research, however, it will be interesting to see how this viewpoint evolves. On the other end of the spectrum are physicians delivering point-of-care therapies with autologous cells, who argue that point-of-care therapies help fuel medical innovation and can be adequately regulated by state medical boards. Here the potential conflict of interest is more evident, with enormous financial incentives tied to stem-cell treatments that can cost in excess of US $20,000. While physician-based societies such as the International Cellular Medicine Society tend to advocate clinical innovation and the delivery of therapies under the scope of the practice of medicine, this vision is sullied by images of rogue clinics that operate without regard for patient safety or benefit [106] . future science group
Industry plays an important role in this ethical and legal debate, as their (typically) allogeneic products may be threatened by autologous, point-of-care therapies. In theory, allogeneic products should be cheaper to manufacture and administer than autologous therapies. However, the extensive costs associated with FDA regulation and manufacturing oversight of massproduced allogeneic cells may negate these theoretical cost savings. With no clear efficacy benefit for most patient populations, point-of-care, autologous therapies represent a real threat to the penetration rates most commercial entities project. This makes for strange bedfellows, as industry lobbies for tougher regulations for point-ofcare therapies in an effort to create a more significant barrier to entry for autologous therapies offered by these physicians. Caught in the middle of competing stakeholders these three is the FDA, trying to balance clinical innovation with their mandate from Congress to maintain public safety. Perhaps most importantly, we must consider this situation from the perspective of the patient. Fueled by wild promises of efficacy and fantastical images in the lay press, it is no wonder that desperate patients look to stem cell therapies for hope. With few objective tools to help guide them, the situation is primed for disappointment and potentially unnecessary health risks. Unequivocally, the situation as it exists today is a disservice to patients, and creates an economic sinkhole for the federal government. While we sink billions into federally funded research, few therapies reach the clinic to make a positive impact on public health. Meanwhile, Americans funnel hundreds of millions of dollars to offshore clinics. The real problem with point-of-care autologous therapies, however, is not the risk of communicable diseases or tumorigenesis, for example – those risks are easily mediated by reasonable manufacturing and safety measures, and generally lower than alternative www.futuremedicine.com
therapies. Indeed it is puzzling to contemplate, for example, the FDA’s concerns with tumorigenesis for stem cell treatments targeted at congestive heart failure. Given the safety and efficacy that both autologous and allogeneic stem cells have demonstrated for myocardial regeneration, it is remarkable that only a few thousand patients have been treated in the USA and EU since the first human use more than a decade ago. Meanwhile, approximately 200,000 Americans are dying every year from congestive heart failure or complications of myocardial infarction awaiting the outcome of this debate [18] . Given the lack of alternatives for these patients, it is unforgivable that CBTs have not been made more readily available. While critics understandably point to the poor risk–benefit ratio associated with less scientifically justifiable treatments, it is puzzling to see the same arguments applied to clinics performing orthopedic procedures, myocardial regeneration, lower limb angiogenesis, for example. The fundamental problem, then, is that there are few tools by which regulators or patients can objectively measure risk–benefit. For allogeneic therapies, it is difficult to contemplate a major shift in the existing regulatory framework. While there are a variety of ways to streamline the overall review process without introducing undue risk, the FDA rightfully looks at these allogeneic products as mass-produced technologies, and puts significant manufacturing and quality assurance hurdles in place to minimize the risk of product failures that can affect thousands of patients. For autologous, point-of-care therapies, however, it is difficult to make the same argument. Despite the various perspectives, incentives and biases outlined above, there are several points that most experts would objectively agree upon: The restrictive FDA regulatory framework, as it exists today, is a significant driver in building ‘stem cell tourism.’ As opposed to developing a streamlined process for evaluating the 95
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safety and efficacy of autologous therapies, it drives patients to clinics abroad, outside of the legal and regulatory oversight and authority inherent within the US healthcare system; Autologous therapies do not represent a public health risk in the same sense as a mass-produced drug, but rather, represent a risk more akin to a surgery than a drug; It is neither cost–effective nor feasible to expect the same manufacturing quality controls for autologous therapies as those in place for mass-produced allogeneic therapies (just as one would not expect the same quality control burden in an operating room as in a device manufacturer’s clean room); The risks associated with the nonhomologous delivery of adult, autologous cells (i.e., cancer, cell aggregation-induced embolism or stroke, ectopic tissue formation, disease transmission), while not zero, is exceptionally low in practice and largely theoretical at this point; With the exception of maintaining sterility, the risks associated with short-term expansion (through ~p5) are relatively low and can be managed effectively through the use of closed loop systems or modest QA programs; While efficacy may vary with cell purity or dosing, there is little risk from a safety perspective in delivering a mixed population of autologous cell types across a wide range of dosages. Similarly, there does not appear to be a safety issue associated with cell-viability; The tolerance for risk in target patient populations is directly linked to the severity of the disease and the likelihood of recovery with standard medical therapy; While there is a precedent for regulating CBTs under the practice of medicine (i.e., in vitro fertilization [IVF]), there is no state medical board framework in place today to train or
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monitor physicians in the safe isolation and delivery of CBT; Few prospective patients are adequately informed of the potential risks and benefits associated with CBTs; While those in the field may assign various values to animal studies, many would agree that animal studies are not as predictive of human safety or efficacy as the FDA might suggest. Animal studies with CBTs do disappointingly little to alleviate risk or convey efficacy in human models, and there is no real substitute for slow, measured progression through initial human studies. While admittedly a controversial concept, it is more likely that the most efficacious protocols will be derived from careful, controlled and monitored human studies rather than a Geron-like progression through hundreds of rodent studies. These points do not, however, in any way condone the unregulated free-forall that has evolved in many parts of the world. Rather, we propose a new system that recognizes the strengths and weaknesses of classic drug clinical trials, values physician innovation and strives to balance patient risk with potential benefit. This new regulatory framework would mimic elements of the FDA’s existing tiered structure (Class I, II and III), recognizing the risk–benefit differences between a marrow-derived injection for critical limb ischemia and intravenous injections for vague afflictions such as ‘aging’. It should not, however, preclude largely investigational therapies for debilitating diseases, such as Parkinson’s or Alzheimer’s, even though there may be relatively little evidence for efficacy. Indeed this type of controlled clinical ‘experimentation’, though largely absent in the USA now, has driven some of the most prolific periods of medical innovation. It would, however, require appropriate quality control guidelines, and perhaps most importantly, establish reporting requirements for data collection. Whether under the umbrella Regen. Med. (2012) 7(6 Suppl.)
of the FDA or State Medical Boards, we would establish a regulatory framework for autologous therapies that establishes: Basic quality assurance guidelines to target the most prominent risks associated with manipulating cells (training, tracking, sterility, crosscontamination). These guidelines would require GMPs akin to those used in IVF but would not encumber a physician to perform years of benchtop research to identify the optimal cell concentration, cell population ratios and mechanistic data; A tiered risk–benefit ratio for all therapies that would drive a consistent informed consent process. A patient would clearly understand the differences in efficacy for treatments for Alzheimer’s or Parkinson’s versus those for myocardial regeneration or critical limb ischemia; An independent accreditation process to give patients a tool to seek only physicians who have been adequately trained in the harvest, processing and delivery of cells and whose facilities and protocols have been properly evaluated; A mandatory data collection registry that captures patient outcome data and that would be shared with healthcare authorities to monitor different protocols for differential evidence of safety and efficacy. Over the last 5 years, thanks in large part to an alarmist focus on largely hypothetical risks, autologous stem cell therapies delivered under the umbrella of the practice of medicine have been portrayed as ‘snake oil’. While there is admittedly no shortage of examples where this image is true, it is clear that this broad brush should not be used to paint the entire field. Moreover, the real risks do not need to be managed by a regulatory framework designed for mass-produced, allogeneic therapies. Sadly, some of the US clinics that have developed ideal models for quality assurance systems and safety controls have been attacked and derided future science group
Autologous cell therapies: challenges in US FDA regulation
for failing to live up to FDA investigational new drug application standards. These illogical and counterproductive attacks simply drive patients abroad where standards are nonexistent. Our objective should be to allow US-based stem cell clinics to deliver therapies with reasonable safeguards (that are not the same as drug manufacturers, and do not strive for zero risk) to adequately informed patients in a transparent fashion. Assuming that allogeneic and autologous treatments should be regulated the same is a disservice to patients everywhere. Ultimately this debate has many parallels with the evolution of organ transplantation. Imagine today, the barriers a physician would face in developing successful transplantation protocols under the framework of the
FDA. Indeed, physician innovation and significant clinical risks were certainly a major driver behind the success that the field enjoys today. Arguing against point-of-care therapeutics while holding up the sensationalistic banner of rogue clinics is a bit like trying to curb the transplantation field over concerns of organ trafficking. While one can debate ad nauseam over whether the FDA or state medical boards can best manage an improved regulatory framework, it would seem clear that the FDA’s existing framework works poorly for these autologous applications. State medical boards, have, in contrast, proven quite effective at delivering other CBTs as exemplified by the IVF model [19] . Irrespective of which agency acts as the watchdog, it is clear that
an improved system with a rational policy toward risk–benefit would be a dramatic benefit to patients. As we contemplate the structure of new regulatory frameworks, we must be mindful of the very clear financial conflicts of interest held by industry, the physicians and academia.
Financial & competing interests disclosure The authors are employees of Cytograft Tissue Engineering, Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
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clinic. Nature 466(7309), 909 (2010). 14 Cyranoski D. FDA’s claims over stem cells
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regulate your cells. Wall Street Journal 7 August (2012). 16 Philippidis A. Stem cell tourism hardly a
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IntelliCell Biosciences. www.fda.gov/ICECI/EnforcementActions/ WarningLetters/2012/ucm297245.htm (Accessed 23 August 2012). 104 Malarkey MA. FDA warning letter to
Thomas E Young LLC. www.fda.gov/ICECI/EnforcementActions/ WarningLetters/2012/ucm301620.htm (Accessed 23 August 2012). 105 ISSCR emphasizes rigorous oversight for
application of stem cell based treatments. www.isscr.org/ISSCR_emphasizes_ rigorous_oversight_for_application_of_ stem_cell_based_treatments/4573.htm (Accessed 23 August 2012). 106 Pelley S. 60 minutes: stem cell fraud.
9 January (2012). www.cbsnews.com/video/ watch/?id=7394380n (Accessed 24 August 2012).
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fertilization and the law. Fertil. Steril. 42(3), 348–355 (1984). www.futuremedicine.com
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Ministry of Education, Culture, Sports, Science and Technology (MEXT)
POLICY, REGULATION & ETHICS
opinion Autologous cell therapies: the importance of regulatory oversight Michael Werner, Tim Mayleben & Gil Van Bokkelen* Promising new medical technologies and approaches to treatment offer the potential to substantially improve the lives of patients who need help, and in some cases transform the way medicine is practiced. In recent years, the biotechnology industry has generated many examples of new approaches that are having a profound impact on medical care, including protein and peptide therapeutics, monoclonal antibodies and molecular diagnostics.
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Few would argue that the regulatory landscape doesn’t need improving, and we must continuously be thinking about ways to make it clearer, more predictable and more efficient, including refining the definitions used to determine regulatory oversight.
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Many regard the field of cell therapy in regenerative medicine as having transformational potential – capable of substantially improving medical outcomes, enhancing patient (and family) quality-of-life and ultimately reducing overall healthcare costs. Over the past decade, we have seen an explosion in the number of peerreviewed publications exploring the biology of various stem cell populations, and evaluating their use in a range of preclinical disease models. Furthermore, we have seen consistent growth in the number of programs advancing into clinical trials, using both autologous and allogeneic-based cell therapy approaches (Table 1). Despite this, some argue that progress has been slowed by an overly burdensome regulatory framework imposed by the US FDA. While some FDA reforms are needed it is worth remembering that the majority of experimental therapies are ultimately found wanting during clinical trials. In some cases, promising candidate therapies do not actually help
Michael Werner, Athersys, Inc., (NASDAQ: ATHX), 3201 Carnegie Avenue, Cleveland 44115-2653, OH, USA Tim Mayleben, Athersys, Inc., (NASDAQ: ATHX), 3201 Carnegie Avenue, Cleveland 44115-2653, OH, USA *Author for correspondence: Gil Van Bokkelen, Chairman & CEO, Athersys, Inc., (NASDAQ: ATHX), 3201 Carnegie Avenue, Cleveland 44115-2653, OH, USA
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patients in a consistent or meaningful manner, or may pose unexpected safety issues that are only identified during the conduct of rigorous clinical studies. Even substances that naturally exist in the human body are not guaranteed to be safe and effective when they are used as therapies. In fact, while biologics have shown a meaningfully better clinical success rate than pharmaceuticals, only a minority of new biologic treatments are ultimately proven to be both safe and effective – approximately one in four, according to the BioMedtracker study results that were released in February 2010. This project, which analyzed over 4275 drug development programs in various stages of clinical development from October 2003 to December 2010, found that approval rates for lead indications among biologics was 26 versus 14% for other new molecular entities (and substantially lower for secondary indications in both categories). Some have argued that a restrictive regulatory landscape in the USA has led many groups to conduct clinical trials internationally, foregoing trials that involve FDA oversight, thereby leading to a severe reduction of domestic clinical activity. However, an analysis of both autologous and allogeneic cell therapy-based approaches demonstrates
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that since 2000, there are a substantial number of FDA-authorized clinical trials using stem cells that involve clinical institutions in the USA, and that the number of such trials has grown over time. While international clinical activity regarding stem cell therapies has also grown substantially, there clearly is no barrier to entry for sponsors who wish to conduct clinical studies in the USA (or in Europe, where the regulatory framework is generally regarded as being similar to that in the USA) (Figure 1). The Center for Biologics Evaluation and Research is the center within FDA that regulates biological products for human use under applicable federal laws, including the Public Health Service Act and the Federal Food, Drug and Cosmetic Act. FDA regulations for cell therapies are designed to promote safe collection, manufacture, storage and use of human cells, and cellular- and tissuebased products (HCT/P). These regulations can be found at 21 CFR. Parts 1270 and 1271 (note that The Center for Biologics Evaluation and Research does not regulate the transplantation of vascularized human organ transplants, such as kidney, liver, heart, lung or pancreas). FDA regulations of HCT/Ps include comprehensive requirements to prevent the introduction, transmission and spread of communicable disease. To be exempt from FDA regulatory oversight HCT/Ps must meet criteria set forth in the Public Health Service Act. FDA defines ‘manufacture’ as “any or all steps in the recovery, processing, storage, labeling, packaging or distribution of any human cell or tissue, and the screening or testing of the cell or tissue donor”, as described in 21 CFR. 1271(e). To be exempt the HCT/P must be: minimally manipulated; intended for homologous use as reflected by the labeling, advertising or other indications of the manufacturer’s objective intent; not be combined with a drug or device; future science group
Table 1. Number of clinical trials listed on ClinTrials.gov analyzed by trial start date according to the year of indicated initiation. Year
Autologous trials initiated
Allogeneic trials initiated
2012†
22
22
2011
50
23
2010
47
12
2009
45
15
2008
30
18
2007
34
10
2006
29
10
2005
32
6
2004
23
5
2003
12
14
2002
13
9
2001
12
17
Numbers for 2012 indicate trials initiated through mid-year. Data from [1]. †
not have a systemic effect and not be dependent on the metabolic activity of living cells for its primary function except if for autologous use, allogeneic use in a first-degree or second-degree blood relative, or reproductive use. Additional components of the FDA’s regulation of HCT/Ps are found at 21 CFR 1271. The concept of what constitutes appropriate regulatory oversight was the central issue in a recent ruling by the United States District Court for the District of Columbia in United States v. Regenerative Sciences LLC. This case raised important questions about the extent of the FDA’s jurisdiction over procedures where autologous cells (a patient’s own cells or tissues) are administered in a physician’s office, clinic or a hospital. At the heart of the argument is whether such treatments are ‘biologic medicines’ (also known as a ‘biologic’ or a ‘biological product’), that should require human clinical trials to demonstrate safety and efficacy and be regulated by FDA. In autologous cell therapy, where cells are isolated from the patient for subsequent readministration to the patient, the FDA has stipulated that in www.futuremedicine.com
some circumstances, no clinical trials are required. Specifically, this is the case if the cells or tissue that have been harvested from the patient meet the standard of ‘minimally manipulated’ and the cells are being used in a ‘homologous manner’. For autologous therapies that do not meet the definition of minimally manipulated, and/or that are not being used for a homologous biological purpose, the FDA has deemed it appropriate to require clinical trials to establish safety and efficacy. Key to understanding whether FDA regulations apply are the concepts of ‘minimally manipulated’ and ‘homologous use’. The FDA defines ‘minimal manipulation’ in the following manner: “…[f]or cells or nonstructural tissues, processing that does not alter the relevant biological characteristics of cells or tissues” (see 21 CFR 1271.3(f)(2)). While the FDA has issued some guidance on the minimal manipulation of structural tissue, no such guidance has been issued to define the minimal manipulation of cells. However, in a proposed approach issued in 1997, the Agency stated that “processing of cells and nonstructural tissues to be more-than-minimal manipulation when the processing 101
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alters the biological characteristics (and thus potentially the function or integrity) of the cells or tissue, or when adequate information does not exist to determine whether the processing will alter the biological characteristics of the cell or tissue. Examples of morethan-minimal manipulation of cells and tissues include cell expansion, encapsulation, activation, or genetic modification” [Docket Number 97N-0068]. FDA regulations define ‘homologous use’ as “the repair, reconstruction, replacement, or supplementation of a recipient’s cells or tissues with an HCT/P that performs the same basic function or functions in the recipient as in the donor” (see 21 C.F.R. 1271.3(c)). The transplantation of hematopoietic stem cells obtained from bone marrow or the peripheral blood for the treatment of leukemia is an example of homologous use, and is a treatment that has been used and studied for more than 40 years.
Some argue that this regulatory treatment of autologous cell therapies may be contrary to good medical practice. They say physicians must be allowed to use their judgment to develop and administer new cell therapies outside of the clinical trial process – similar to other experimental surgical or medical procedures. Clearly, there needs to be some room for investigator-driven innovation in medical practice, and physician-sponsored clinical studies. However, it is also important to ensure that patients are being adequately informed with regard to the true risks and benefits of a potential treatment – especially when they are asked to pay for it. Unfortunately, while in general there is an outstanding record of safety associated with autologous cell therapies, there are a few examples where a patient’s own cells have been readministered for something other than a homologous biological purpose, in which the patient was inadvertently harmed, or even died,
as a result. These types of events could reflect a lack of training or knowledge that could be gained from formal clinical trials, and underscore the need for some form of rigorously controlled studies and regulatory oversight. It should not be assumed that just because the cells are derived from the patient that the approach is perfectly safe, the physician and patient are both adequately informed, and nothing bad can happen. Few would argue that the regulatory landscape doesn’t need improving, and we must continuously be thinking about ways to make it clearer, more predictable and more efficient, including refining the definitions used to determine regulatory oversight. Recent progress should help create a clearer and more efficient regulatory path for sponsors attempting to develop new therapies designed to address significant unmet medical needs. In July, Congress passed and President Obama signed the Federal Drug and
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Figure 1. Geographic distribution of clinical trials that have been registered on ClinTrials.gov since January 2000 that are listed as involving stem cells as an interventional part of the therapy. Search criteria exclude gene therapy trials. 102
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Safety Innovation Act, which included a renewal of the Prescription Drug User Fee Act. This legislation included important new provisions intended to speed clinical development in areas of great medical need. Specifically, it includes a broadening of the ‘accelerated approval’ pathway, and the creation of a ‘breakthrough therapies’ category for promising new medicines. Both frameworks are designed to reduce the length, cost and complexity of clinical trials, while also protecting patient safety. Taken together, these provisions are likely to greatly facilitate rapid development and commercialization of regenerative medicine and cell therapies, so that patients can be helped. Current regulations balance protecting public health by requiring data demonstrating that certain uses of cells are safe and effective. How they are applied will likely change over time as science advances and researchers – and the FDA – learn more about the biological properties of certain cell and tissue based therapies. The regulatory and clinical trial process is intended to ensure public safety during this time of scientific advancement.
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But companies that promote cell and tissue ‘therapies’ not demonstrated to be safe and effective are really only marketing risk, veneered with unsubstantiated promises. When adverse events happen under those conditions, all patients are hurt because it slows the field, delaying the development of safe and effective cures and treatments. Thoughtful, rigorous science will ultimately bring safe and effective products to patients. Physicians must always be empowered to do whatever they lawfully can and use their best medical judgment to help patients. But ultimately, patients need their physicians to have access to numerous safe and effective therapies to treat their disease or condition. The best – and fastest – way to achieve that goal is to ensure that cell therapies undergo rigorous testing. The prospect of new regenerative treatments and even cures where current medicine and therapies offer little hope for the patient is thrilling. The very promise of regenerative medicine illustrates the need for regulation:
www.futuremedicine.com
for where there is promise science provides protection against false hope. A rigorous clinical trial system will ensure that safe and effective products, especially those with transformational potential, reach patients quickly.
Financial & competing interests disclosure G Van Bokkelen is employed as Chairman and CEO by, owns shares in and has options with Athersys. T Mayleben is CEO at and holds financial interest in Aastrom. M Werner is a partner at Holland & Knight, a law firm that represents numerous companies in the regenerative medicine sector. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
Website 1
ClinicalTrials.gov http://clinicaltrials.gov
103
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POLICY, REGULATION & ETHICS
Perspective Pay-to-participate funding schemes in human cell and tissue clinical studies Douglas Sipp* Funding support for clinical research is traditionally obtained from any of several sources, including government agencies, industry, not-for-profit foundations, philanthropies and charitable and advocacy organizations. In recent history, there have also been a limited number of cases in which clinical research programs were established in which funding was provided directly by patients in turn for the ability to participate as nonrandomized subjects. This approach to clinical research funding, which I refer to here as the ‘pay-to-participate’ model, has been both criticized and rationalized on ethical grounds, with reference to its implications for issues, including equipoise, therapeutic misconception, justice, autonomy and risk– benefit balance. Discussion of the scientific implications of this funding scheme, however, has been more limited. I will briefly review the history of the pay-to-participate model in the context of experimental cell and tissue treatments to date and highlight the many ethical and, particularly, scientific challenges that unavoidably confound this approach to the funding and conduct of clinical research. Keywords: biomedical ethics n clinical research n equipoise n fee-for-service n therapeutic misconception
The history of an unusual idea Clinical research, in which experimental interventions are tested in human subjects for properties such as safety, dosage and efficacy in the treatment of specific medical conditions, has a long and fraught ethical history. The Nuremberg Code, established in 1947, was the first internationally ratified document governing the ethical conduct of human medical research [101] . In subsequent years, additional guidance documents, including the Declaration of Helsinki (World Medical Association, 1964) [1] , the Belmont Report (National Commission for the Protection of Human Subjects of Biomedical and Behavioral Research, 1978) [2] and the International Guidelines for Biomedical Research Involving Human Subjects (Council for International Organizations of Medical Sciences, 2002) [3] have expanded on and refined the principles first espoused in the Nuremberg Code. These include beneficence/nonmaleficence, respect for
persons, autonomy, informed consent, protection of rights and justice.
risk–benefit balance, as outlined in greater detail below.
Interestingly, while many of these ethical doctrines extensively discuss issues arising from the payment or other forms of compensation of human research subjects, such as undue influence and the risk of exploitation of vulnerable subjects, no passage in any of the primary literature cited above addresses the ethics of requiring, inducing, encouraging or allowing patients to pay for their own participation in a clinical research study. It may be that in the first decades of biomedical ethics following the promulgation of the Nuremberg Code there was no perceived need to address this situation, despite the clear ethical tensions inherent in such an approach to research funding, which include fair subject selection, maintenance of equipoise, potential exacerbation of therapeutic misconception and placebo amplification, and skewing of the
There do exist several forms of clinical study in which patients acting as research subjects have been expected to make some financial contribution or payment. In the USA, the FDA makes provisions for treatment investigational new drugs (INDs), emergency INDs, parallel track studies and various openlabel or open-protocol studies as part of its efforts to allow for ‘expanded access’ to investigational agents prior to the completion of a phased clinical trial. In the case of the treatment IND, subjects with life-threatening or untreatable diseases may be able to pay to obtain access to investigational drugs that have been shown to have adequate safety and for which data suggestive of efficacy is available [4] . Importantly, however, the US government does not recognize such access as a fundamental right [5] , due to the experimental, and thus uncertain, nature of investigational agents, and in any case such access may only be granted for agents already under investigation in a formally registered trial and with the approval of the trial
*Author for correspondence: Science Policy and Ethics Studies Unit, RIKEN Center for Developmental Biology, 2–2–3 Minatojima Minamimachi, Chuo-ku, Kobe, 650– 0047, Japan; Tel.: +81 78 306 3043; Fax: +81 78 306 3090; sipp@cdb.riken
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sponsor and regulatory authority. It is also important to note that while the primary focus of the clinical trial in such cases continues to be research, the investigational agent is taken out of that context and for exceptional limited use as a potential treatment. Other forms of patient-supported research are also known. Numerous not-for-profit organizations fund and organize research in disease areas of interest, working with academic and industry partners to conduct rigorously designed clinical studies. This may be particularly advantageous in supporting clinical research into medical conditions affecting relatively small numbers of patients or involving the use of unpatentable interventions, which might otherwise be neglected by industry. A group of multiple sclerosis patients, for example, recently funded a study of low-dose naltrexone conducted by clinical scientists at UCSF [6] , and numerous advocacy groups and foundations have organized funding drives that provide supplementary research funds for target conditions. At least one private company, CollabRx, has been established to provide support and coordination for patient-sponsored clinical research [7] . In these patientsupported funding models, however, the organizations collecting the financial donations and those conducting the clinical research typically remain independent of each other, and there does not appear to be any linkage at the individual level between making a financial contribution and eligibility to participate in a sponsored study. For these reasons, I refer to clinical research funding approaches in which there is a direct relationship between financial payment or donation by an individual patient and the enrolment of that patient in the study in question as ‘payto-participate,’ rather than the broader ‘patient-funded,’ which could include unproblematic research efforts in which groups of patients provide all or part of the funding for clinical studies in which eligibility is not tied to payment. With 106
the exception of historical contexts, I also avoid the use of ‘fee-for-service’ to describe such funding mechanisms, in that any description of research as a ‘service’ (which itself is a debatable conceptualization), should more explicitly acknowledge the contributions of human subjects, rather than portray them simply as paying consumers. The 1980s saw the advent of several businesses in which the research funding scheme called on patients to pay fixed amounts to ensure their place in generally open-label research programs. In 1985, the Tennesseebased private company Biotherapeutics introduced this novel funding model for what it described as clinical studies into cancer treatments using personalized monoclonal antibodies, in which patients paid up to US$35,000 to participate as research subjects. This funding model was frequently referred to at the time as ‘fee-for-service’ clinical research. The company enjoyed some early success in establishing collaborations with scientists at major research universities and institutes, but was unable to secure sufficient funding to sustain its business model and had effectively ceased operations by 1989 [8] . At about the same time, a separate company in California, Solo Research, began marketing access to an investigational drug for the treatment of Alzheimer’s that had not been approved by the FDA [9] . The FDA conducted an investigation of the proprietor of Solo Research for this practice, as it relied on an imported drug (one which in fact later received marketing authorization following testing in a registered clinical trial conducted by a different company) [10] , whereas the FDA took no action against Biotherapeutics, evidently on the grounds that the business did not cross state lines [11] . Although neither Biotherapeutics nor Solo Research was engaged in transplantation of human cells or tissues, I have included them here for historic reasons, as they established precedents that triggered Regen. Med. (2012) 7(6 Suppl.)
extensive discussion of this clinical research funding model at the time, and are direct antecedents of businesses that have offered similar pay-to-participate trials in the human cell and tissue therapy arena. Several investigational uses of human cell and tissue products have also been offered to patients on a payto-participate basis. After entering bankruptcy following the failure of its monoclonal antibodies business, Biotherapeutics was resurrected as a new oncology franchise, Response Oncology, specializing in high-dose chemotherapy plus autologous bone marrow transplantation for late-stage breast cancer patients, at a time when several registered clinical trials of this protocol were still underway [12] . The results of clinical trials revealed that the protocol employed by Response and several other commercial enterprises was no more effective than placebo, but only after several tens of thousands of women had been subjected to this expensive and unnecessary procedure. Also in Tennessee, neurophysiologist Peter Law established the Cell Therapy Foundation, a not-for-profit organization that offered experimental open-label injections of myoblasts to Duchenne’s muscular dystrophy patients [13] , in some cases charging several thousands of dollars for access to patients overseas [102] . Similarly, numerous programs in the USA and Mexico conducted research into the use of allogeneic fetal tissue grafts [14] and autologous adrenal medullary transplants [15] in the 1990s, for which patients are reported to have paid tens of thousands of dollars [16] . A number of organizations have also conducted ‘fee-for-service’ or ‘patientfunded’ clinical research into stem cellbased treatments for a range of medical conditions. The Hospital San Jose Tecnologico de Monterrey, a Monterrey, Mexico-based organization with an emphasis on medical tourism, conducted clinical studies testing peripheral bloodfuture science group
Pay-to-participate funding schemes in human cell & tissue clinical studies
derived CD133 + cells for the treatment of amyotrophic lateral sclerosis [17] , in which patients were encouraged to subsidize the research through financial donations of up to US$18,000 (it was possible, however, for prospective subjects to waive the contribution if they were unable to pay) [103] . Also in Mexico, the Regenerative Medicine Institute (RMI), an organization affiliated with Angeles Hospital International in Tijuana, has introduced ‘patient-funded clinical trials’ of various stem cell interventions, in which individual patients are asked to pay thousands of dollars to participate as subjects in open-label studies of stem cells for a wide range of medical conditions, as indicated in descriptions such as ‘Here at Angeles Health we offer patient funded stem cell therapy trials for COPD, heart conditions and many other health problems’ [104] ; notably, the very phrase “stem cell therapy trials” is highly suggestive of a conflation of research with care, which lies at the heart of therapeutic misconception. One website associated with the RMI, StemCellMX [105] until recently featured a menu of experimental stem cell treatment options for heart, vascular, visual, neurodegenerative, metabolic, lung, orthopedic, autoimmune, renal, and hematologic conditions, as well as for various cancers, for which costs ranged from US$7500–35,000 (data archived by author). In addition to these two clinical organizations in Mexico, a large number of companies have advertised ‘experimental’ stem cell interventions in which the primary emphasis was more clearly on patient care, rather than research. Several of these have also registered clinical trials with various authorities subsequent to treating large numbers of patients [106,107] , but I have been unable to determine whether in these cases patients were asked to participate in such trials. At least one US-based company, TCA Cellular Therapy, was sent a warning letter by future science group
the FDA for a host of protocol violations in the conduct of registered IND studies, including the administration of investigational stem cell products to individuals not enrolled in the IND trials [18] , but again there is no clear record of human research subjects being asked to pay to participate in the clinical trials sponsored by this organization.
Scientific validity & ethical principles Several analyses of the ethics of payto-participate clinical research have been published to date. Due to space constraints, I will only summarize their conclusions here, but I do so with strong encouragement to interested readers to seek out and compare the articles cited. Lind briefly noted the establishment of a company (Biotherapeutics) that had begun marketing ‘fee-for-service’ research into individualized monoclonal antibodies for cancer treatment, and, while raising and examining the arguments for and against such an approach, suggested that ‘criteria for approving a patient-funded trial should be more stringent than those applied to the usual sorts of clinical trials’ [19] . In an earlier commentary, Lind suggested that while it may be appropriate to ask patients to pay for ‘informal’ studies (which he defined as those in which ‘a physician uses, on an ad hoc basis, a novel treatment when no standard therapies are available that might reasonably be offered to a patient’), it is important in such cases to account and control for the introduction of risks and biases due to the pay-to-participate study design, specifically including psychological risks to the patient-subjects, and economic biases in enrolment and interpretation of results [20] . Robert Oldham published a rationale in favor of ‘fee-forservice’ research in the cancer context, citing individual freedom to choose and ethical equivalence with industryfunded clinical studies in defense of the already controversial funding scheme; it should be pointed out that Oldham was also the founder of Biotherapeutics, www.futuremedicine.com
the company many cite as the first to introduce this funding model [21] . The most comprehensive analysis to date of the arguments for and against patientfunded research appears to be that by Morreim, in which the author addresses and for the most part dismisses the threats posed to patients, the risk of inequalities in opportunity to participate for financial reasons, and the hazards to scientific research, concluding that ‘it may be quite appropriate to permit patient-funded research’ provided that appropriate standards are in place to ensure similar levels of scientific quality and patient safety to those observed in research funded by traditional means [22] . Evans and Block looked specifically at the ethical issues in patient-funded clinical research in the context of ‘complementary medicine,’ such as the assessment of disease prevention by dietary supplements, and concluded that ‘a strong ethical case may be made for the appropriateness and value of significantly expanded fee-for-servicesfunded research’ in such contexts [23] . Lastly, a report issued in 1987 by the US government Office for Technology Assessment (‘New Developments in Biotechnology: Ownership of Human Tissues and Cells’ noted the recent emergence of the ‘fee-for-service’ clinical research funding model, but focused primarily on ownership of human biological materials in this context, and did not comment on the ethicality or viability of the model [24] . This is not to suggest that the payto-participate funding model has not occasioned controversy as well. In one published comment, an editor of The New England Journal of Medicine, Arnold Relman, said of Biotherapeutics ‘It’s cruel deception. It’s commercial exploitation of a tragedy. I think it’s totally immoral.’ [11] . The New York Times published a lengthy article on the same company, highlighting the concerns of several researchers that the pay-to-participate scheme would affect quality of the research design, inequalities in access and risk of patient exploitation [25] . 107
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As we can see from the above, there has been significant discussion and indeed support on the part of several previous commentators for the notion that clinical research can in certain cases justifiably be funded directly by patients seeking to participate as subjects. It should also be noted as well that media reports from the time noted significant ethical controversies, and included views voiced by prominent ethicists that were critical of the pay-to-participate model; these critical views, however, do not appear to have been developed into peer-reviewed publications. Those expressing positive views have typically emphasized concepts of individual freedom to choose and ability to consent, laissez-faire regulation on the part of the government, lack of funding alternatives and substantial equivalency with other forms of research funding in support of their positions. In my view, however, the scientific implications of the pay-to-participate funding model have yet to be discussed adequately, and as these have important consequences for the ethical viability of the model, I have chosen to highlight some of the more salient issues below. Prescriptive approaches to the ethics of clinical research have placed increasing emphasis on the primary importance of scientific validity [26] , along with more traditional values such as beneficence, respect and justice. The International Ethical Guidelines for Biomedical Research Involving Human Subjects, for example, specifically states that ‘scientifically invalid research is unethical in that it exposes research subjects to risks without possible benefit’ [3] . What then does this mean for pay-to-participate funding mechanisms? The first set of scientific issues center on experimental design, as it seems intuitively clear that many patients would object to paying large sums to participate in studies in which they were subject to the uncertainties introduced by such standard experimental design 108
features as randomization and blinding. This inherent incompatibility between standard experimental controls and the pay-to-participate model would appear to make this funding mechanism only appropriate for less rigorous, preliminary forms of research, such as open-label and individual case studies, raising legitimate questions about their scientific value. Notably, however, open-label studies are generally conducted in academic settings and represent a first step toward more rigorously controlled research, rather than the basis of a business model in which continued recruitment of paying patients is a primary revenue source. That distinction notwithstanding, there are potential issues in recruitment or selection bias for studies funded in this manner as well, given that more seriously ill patients may have exhausted their savings, thus rendering themselves unable or ineligible to participate in such studies due to lack of funds. Conversely, patients with the financial ability to pay may represent a healthier population than those with more severe illness, or may use their greater resources to obtain a greater variety or quality of co-interventions than less wealthy patients. Such effectively selective inclusion of healthier subjects, or exclusion of less healthy ones, could bias the results of such studies toward greater efficacy than might be observed in the general population. Some approaches, such as the study of a stem cell treatment for amyotrophic lateral sclerosis at Tec de Monterrey, have made donations voluntary, and allowed patients to seek exemptions based on financial need, but information on such allowances in similar commercially oriented research programs is scant, and several analyses have raised specific justifications for studies in which ability to pay is an inclusion criterion, as described in detail below [21,22] . The pay-to-participate model may have serious consequences on the interpretation of results as well, Regen. Med. (2012) 7(6 Suppl.)
as the very act of paying is likely to establish a notion of the ‘value’ of the opportunity to participate, and indeed of the intervention under study. One recent report of value influences on placebo effects showed that even small differences in the perceived monetary value of otherwise identical inactive placebos resulted in significant differences in the pain relief reported by test subjects, with those who were told that they were receiving (placebo) pills of supposedly higher value reporting greater relief [27] ; such effects of value perception on expectation is well documented in numerous other areas as well [28] . It appears, therefore, that value associations, particularly when these involve payments of tens of thousands of dollars, would tend to skew the results of any research funded directly by study participants. While it might be argued that placebo effects associated with the perceived advanced nature of the technology under investigation, or simply due to the sense of investment felt by research subjects, is an issue in many studies, the additional requirement to pay large sums of money is likely to have an additive effect in such cases, exacerbating any underlying predisposition to placebo responses due to other causes. Appropriate design measures, such as comparison against an otherwise identical nonpaying arm, may be necessary to exclude such potentially confounding factors. In human cell and tissue trans plantation particularly that involving stem cells, the need for long-term surveillance must be confronted in any funding model, as bona fide stem cells may survive and continue to function for the life of the recipient. The Guidelines for the Clinical Translation of Stem Cells published by the International Society for Stem Cell Research specifically recommends that human research subjects should be monitored for long-term health effects [29] , and registered clinical trials of novel stem cell interventions typically include follow-up periods future science group
Pay-to-participate funding schemes in human cell & tissue clinical studies
of a decade or more, highlighting the importance of lengthy and vigilant monitoring in protocols involving living cellular agents that may be capable of proliferation, differentiation, migration and paracrine effects even after long periods of quiescence in vivo. From the publicly available information on the pay-to-participate research programs described above, however, it does not appear that any have explicitly provided for such long-term follow-up. Notably, the majority of the organizations that have conducted such research using human cells or tissues in the past three decades have gone bankrupt, been shut down by regulatory authorities or otherwise discontinued their research in these areas, suggesting that the financial viability and sustainability of such business models are important, but overlooked, issues. Of the nonscientific ethical issues confronting pay-to-participate clinical research funding, the maintenance of clinical equipoise and the avoidance of therapeutic misconception are two primary concerns. Clinical equipoise describes the expectation that there be a state of uncertainty on the part of the expert medical community regarding the efficacy or lack thereof of an intervention under investigation [30] , the reasoning being that if the community were certain about the efficacy of an intervention, it would be unethical not to provide it as therapy. Research in which investigators require patients to pay to participate as subjects by necessity walks a tightrope over this divide, in that investigators are required to assign a monetary value to the act of participation in the study on the part of subjects, suggesting to both the physician-investigator and the patient-subjects that there is some inherent value in participation (which could presumably be confused quite easily for advance access to medical care). This warping of equipoise may be further complicated if the participation fee includes a margin for profit on the part of the investigator, which appears future science group
to have been the case in many of the companies that have conducted payto-participate human subject research, as this could result in conscious or unconscious incentives to emphasize positive outcomes, overinterpret neutral ones or overlook neutral ones additional to the potential investigator biases resulting from other nonfinancial causes that are inherent in other research studies.
from exploitative charlatanism. It should be noted that here are certainly cases of open-label studies in which the primary intent is patient care, in which systematic outcome and other data are collected secondarily, but these differ qualitatively from business models in which patients are recruited through marketing efforts to pay to participate in so-called clinical trials or studies, as described above.
Similarly, there would seem to be an unavoidable risk of therapeutic misconception, in which research aimed at developing generalizable knowledge is confused for treatment intended for the care of the individual patient [31,32] . Indeed, an examination of present-day websites advertising ‘patient-funded clinical trials’ reveals that research and therapeutic terms are often used interchangeably, and patient testimonials are provided via prominent links on the same webpage. Inappropriate suggestion of therapeutic intent has been shown to be more commonplace in descriptions of stem cell clinical trials than in trials of other modalities, indicating that the field may be particularly susceptible to such conflation; when combined with the demand for payment, such incautious use of language would appear to make therapeutic misconception an inevitability, if not a specifically desired outcome. The confusion of research for patient care is a fundamental concern in the ethics of human subjects research, as it may inappropriately affect decisionmaking, motivation, expectation and perception on the part of subjects. Notably, this issue is even more problematic in the greater context of the underregulated global industry engaged in the marketing of scientifically unsupported stem cell interventions, many of which describe their products and services as ‘experimental,’ while providing no information on the nature of the supposed experiment being conducted. Such misleading language presumably makes it more difficult for patients to distinguish actual research
Another major consequence of the pay-to-participate research funding model is its skewing of the delicate risk– benefit balance inexorably in favor of the investigator (particularly so when the investigator stands to benefit financially from the enrolment of paying subjects) and against the research subjects. In most traditional forms of clinical research funding, human subjects are frequently compensated by free access to healthcare during the study period, or even by financial payments to compensate for physical risks or lost time. Investigators and trial sponsors stand to benefit from access to healthy volunteers or patients meeting the study criteria; this voluntary participation provides the sponsor with opportunity to study the investigational agent under controlled conditions, which may return additional value to both subjects and sponsors in the event it is shown to be safe and efficacious. In the payto-participate model, however, subjects must not only pay upfront and, by giving informed consent, disavow any expectation of efficacy – all of which minimizes the investigators’ financial risks – the subjects must also assume all the physical risks inevitably associated with participation in a research study, which the investigator does not face in any case.
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Conclusion There have been attempts to implement pay-to-participate funding models for clinical research by various commercial and noncommercial entities for the past three decades, 109
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a surprising number of which have focused on human cell or tissue transplantation. To date, such research efforts have largely been unsuccessful, in both scientific and financial terms. The difficulties in experimental design introduced by requiring subjects to pay may not only limit enrolment, but also severely constrain the scientific validity of the investigation. This attenuation of scientific rigor has important secondary effects on the fundamental ethicality of studies funded in this way, independent even of other equally serious ethical issues concerning equipoise and misconception of therapeutic intent. Given the many profound and often disturbing implications of pay-to-participate funding mechanisms for research design, interpretation of results and the ethical treatment of human research subjects, it is unclear whether or how this approach could be justified as an alternative to already established funding mechanisms for the conduct
of clinical research in humans. Any clinical research program that proposes to obtain funding via such a model should therefore be subject to intensive scientific, legal, ethical, regulatory and consumer scrutiny.
Acknowledgments I would like to thank L Turner at the University of Minnesota for critical reading and discussion of an earlier version of the manuscript.
Financial and competing interests disclosure The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter discussed in this manuscript. This includes employment, consultation, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Key points In recent decades, a number of organizations have engaged in clinical research in which patients were asked to pay to participate as subjects. The pay-to-participate funding model has numerous and profound scientific and ethical implications for study design, implementation and analysis. Scientific problems arise from difficulties with experimental controls, randomization, blinding and placebo amplification, among others. Particular ethical problems associated with this funding model include the disturbance of equipoise and the likely conflation of research with medical care (therapeutic misconception). The pay-to-participate clinical research funding model is inherently unlikely to produce either high-quality scientific research or high-quality medical care.
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Interviews The making of an advocate Alan Fernandez The New York Stem Cell Foundation Susan Solomon
Commentary Why the stem cell sector must engage with social media Lee Buckler 10.2217/RME.XX.XX © 2011 Future Medicine Ltd
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Interview
The making of an advocate
Interview with Alan Fernandez We spoke with Alan, Associate Director at the Genetics Policy Institute (GPI), the organizer of the annual World Stem Cell Summit, to find out what led him to devote his career to stem cell advocacy.
Q
How did you come to join the Genetics Policy Institute? I started working with the GPI while I was at Burrill Life Sciences Media Group. Burrill was partnering the Stem Cell Summit produced by the GPI with the Harvard Stem Cell Institute in 2007. In building the network of supporting organizations and sponsors for that meeting, I decided to shift my career focus to nonprofit advocacy. GPI’s Executive Director, Bernie Siegel, was obviously a ‘man on a mission’ and from that Summit in Boston, I felt firsthand that extreme sense of urgency. Where we have an emerging field of stem cells and regenerative medicine that could possibly cure previously untreatable diseases, how can we stand back and let a group with a minority position impose their will on the majority? Where is the collective compassion for the suffering and chronically sick? I decided that I could best live up to my potential and have a better life dedicated to stem cell advocacy, with the goal of changing lives for the better. Where do get your inspiration to be a stem cell advocate? Dealing with those individuals and their family members afflicted with
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chronic disease offers me continuing inspiration. In this journey, I have encountered some really compelling people. Steve and Barbara Beyer carry the spirit of their late son, Ben, whose bravery battling amyotrophic lateral sclerosis was memorialized in a documentary. The Beyers created ALS Worldwide, a wonderful grassroots organization, counseling families dealing with that horrible affliction. My good friend here in Palo Alto is Gary Dawson, who deals with immense physical challenges resulting from cerebral palsy. The Hempel family who created the Addi & Cassi Fund with their precious daughters afflicted with childhood Alzheimer’s disease. There are a hundred more.
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Where we have an emerging field … that could possibly cure previously untreatable diseases, how can we stand back and let a group with a minority position impose their will on the majority?
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The making of an advocate
Alan has focused his career on advancing stem cell sciences and the field of regenerative medicine since 2006. While working with Burrill & Company, he began working with the Genetics Policy Institute (GPI) on the 2007 Stem Cell Summit with the Harvard Stem Cell Institute. He then joined the GPI full-time in 2008. Alan’s skills in business development and marketing were cultivated at companies like Dow Jones, Ziff Davis and Burrill & Company. Earlier in his career, Alan worked in technology and grassroots business communications, working for start-ups and mid-sized companies.
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Advocacy is a participatory sport, not a cerebral exercise. People do things when they become emotionally charged and when they feel threatened that something important is about to be taken away. You are known for being an ‘international man’: how does your background impact your work? Each year, the GPI builds the World Stem Cell Summit from scratch and recruits organizing partners, sponsors, endorsing organizations and media partners from around the world, some 250 in number. In certain ways we are diplomats, circling the globe promoting support for our field. I am the son of an American diplomat, born in Chile and growing up in Romania, Austria, Switzerland, the UK and the USA. I started my career as an intern for Drexel Burham Lambert in their London (UK) office, lived and worked in New York City and eventually migrated to the Bay Area in California. I developed an interest early on in business, government, economics, policy, foreign countries, leadership and communications. It has been a fascinating journey. What is one of our your proudest moments? I started at the GPI as Director of Public Policy Outreach and was promoted to Associate Director in 2011. My role expanded to traveling to a number of future science group
scientific and industry conferences. But it is when speaking with fellow advocates I feel that I have truly found my voice. Last year, I traveled to Peoria, (IL, USA) at the behest of a very brave patient advocate, Joan Snyder, who runs the Central Illinois Parkinson’s group. I spoke to the audience about the need to build a powerful movement to address the obstacles facing our field. The ovation that day meant the world to me. I know I have found my voice and my calling. The GPI has built a prominent coalition supporting embryonic stem cell research. Explain the role of the Stem Cell Action Coalition. The Stem Cell Action Coalition springs from the Stem Cell Action Network, a group of grassroots stem cell activists present at the creation of the policy battles in 2002. The Coalition emerged as an important force in 2010 with the threat of the ‘Sherley versus Sebelius’ court case. Organized by GPI, the coalition includes 75 organizations, diverse scientific and medical societies, medical philanthropies, university programs and patient groups. Through letters of lawmakers, social media, press www.futuremedicine.com
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releases and frequent policy calls with grassroots activists, the Coalition serves as a voice for the stem cell community and as an engine promoting the field of embryonic stem cell research at the federal and state level. The Coalition is grassroots activism at its best. It’s about commitment to taking action and then taking action. How can patients and industry combine to solve problems and advance the field of regenerative medicine? Let’s have some clarity. Advocacy is a participatory sport, not a cerebral exercise. People do things when they become emotionally charged and when they feel threatened that something important is about to be taken away. Those are motivating factors. The healthcare industry, including the emerging cell therapy companies, need to deal with financial and regulatory hurdles. Without the passion and sense of urgency of the patient community behind them, the road will be much longer and tougher for all. Working with patients, who see the future of regenerative medicine as salvation, the combined force can move mountains, by changing laws, forging innovative 115
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collaborations and increasing public awareness. There has to be continuing communication and interaction and a broad recognition that we are one community. A few of our friends seem to forget that one day we will all be touched in some way by a chronic disease – statistics show one in three will be afflicted. We are sitting on technologies that may alleviate a huge amount of suffering for adults and children. If not for ourselves, let’s make it happen for our kids, our friends and humanity at large.
You often speak about the importance of music in stirring the soul of an activist. How does music move you? Consider a rock concert with 10,000 attendees all dancing to the music, all with their arms outstretched holding aloft a flame. Music does stir the soul. I grew up moved by the music of Simon & Garfunkel and John Denver and many others. My favorite is ‘The Eagle and The Hawk.’ Every time I listen to it I am energized.
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Come dance with the west wind and touch on the mountain tops Sail over the canyons and up to the stars And reach for the heavens and hope for the future And all that we can be and not what we are.
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Financial & competing interests disclosure The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
Journal of cell and developmental biology, stem cell research, tissue engineering, and in vitro systems n vitro in vivo in vitro in vivo in vitro n vivo in vitro in vivo in vitro in vivo n vitro in vivo in vitro in vivo in vitro n vivo in vitro in vivo in vitro in vivo n vitro in vivo in vitro in vivo in vitro n vivo in vitro in vivo in vitro in vivo n vitro in vivo in vitro in vivo in vitro n vivo in vitro in vivo in vitro in vivo n vitro in vivo in vitro in vivo in vitro n vivo in vitro in
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interview The New York Stem Cell Foundation
Interview with Susan Solomon We caught up with Susan Solomon, Co-Founder of The New York Stem Cell Foundation, to discuss the role of the Foundation in facilitating some of the top advances in stem cell science in recent years. Susan L Solomon is Chief Executive Officer and Co-Founder of The New York Stem Cell Foundation (NYSCF), a nonprofit organization established in 2005 to accelerate cures through stem cell research. A longtime healthcare advocate, Susan is a founding member and current President of New Yorkers for the Advancement of Medical Research, is on the Executive Committee for the Alliance for Regenerative Medicine, and she has been a member of the Board of Directors of the Juvenile Diabetes Research Foundation, New York Chapter. Susan was also a member of the Strategic Planning Committee of the Empire State Stem Cell Board. In March 2008, Susan received a New York State Women of Excellence Award from the Governor of New York. In September 2008, she received the Triumph Award from the Brooke Ellison Foundation for her work in establishing NYSCF. Prior to founding NYSCF, Susan, an attorney, spent much of her career building businesses. She established and ran Solomon Partners LLC to provide strategic management consulting to corporations, cultural institutions, foundations and nonprofit organizations. She has also held executive positions at MacAndrews and Forbes Holdings and MMG Patricof and Co. She was the founding Chief Executive Officer of Sothebys.com and was President of Sony Worldwide Networks.
Q
What led you to the decision to co-found the New York Stem Cell Foundation in 2005?
I have been involved in medical research advocacy for a long time. A series of events in my personal life gave me a heightened awareness of these issues. I have a son, now grown, with Type 1 diabetes and I had lost my parents to heart disease and cancer. Going through those experiences I saw first hand that while medicine has advanced over the years, we are basically dealing with the same paradigm: the treatment of Type 1 diabetes is the same treatment that was developed when Banting and Best discovered insulin in the 1920s. The insulin is better, the delivery
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method is better, but we are still dealing with the same paradigm. With cancer and heart disease substantial progress has been made, but when you have end-stage congestive heart failure, you do not have good options, when you have lung cancer, you do not have good options. Our understanding of disease is something that until the advent of stem cell research had remained very much a black box. The decision to start The New York Stem Cell Foundation (NYSCF) was based on two things: erratic government support for the most advanced research in the USA and seeing that there really was a giant gap between the work being done at academic institutions, and the
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delivery of pills and treatments on the commercial side.
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The three key priorities we identified were getting young researchers into the field; providing a forum for researchers to discuss their work, and providing the physical facilities and funding to enable research to move forward.
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…a critical priority was to have a stateof-the-art, privately funded laboratory where you could check politics at the door and do the most advanced work.
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We, as a small organization, could never provide the funding that the government can. But what we can do is create a path, resources, fellowship programs and a laboratory, and lead research. We are providing the proof of concept, so that when a public opinion and public funding is available then that work can be scaled up. What are the main priorities of NYSCF? When we started in 2005, we worked very closely with our scientific advisory boards to identify what we thought were the absolutely critical programs that needed to be established in order for this new field to move forward. The three key priorities we identified were getting young researchers into the field; providing a forum for researchers to discuss their work; and providing the physical facilities and funding to enable research to move forward. One clear problem was that because of funding policies in the USA at the time, young researchers were discouraged from going into the field. So we thought it was very important to establish a wellsupported community, as quickly as we could. We wanted to help early postdoctoral researchers: fund them, give them ways to collaborate, and support from top people in the field, so that they could be encouraged to go into the field. To achieve that we set up the NYSCF Fellowship program. This program is now in its seventh year and we have a network of 35 researchers at universities all over the world. They consider each other their best scientific friends, and it is really an extraordinary group. The program has been such a success that 3 years ago we decided to expand it. What became clear is that now that we have young people in the field, they wanted to be able to continue with high-return, high-risk research: Regen. Med. (2012) 7(6 Suppl.)
research that needs to be done and that the traditional funding bodies simply do not fund. So we established the NYSCF Investigator program as a follow-up to the NYSCF Fellowship program. With the Investigator program we support early career investigators within 5 years of completing their postdoctoral training and starting their own laboratory. We support them for 5 years. It is a very generous award, US$1.5 million, and the kind of work that we encourage is high-risk, highreturn. If you are going to try something that is risky, you are going to have to be rigorous in your approach. It is the kind of thing that might not work, but if it does, it will change everybody’s world. We have investigators, like Ed Boyden at MIT, who have invented an entirely new field, real superstars in innovative research. Another priority was to ‘bang a drum loudly’. That is, to host an annual meeting for translational stem cell research, a small meeting where people could present their work prepublication and share their work with senior researchers. We cover a range of diseases each year and offer an opportunity to highlight those researchers who are doing the most exciting work. We are now onto our seventh conference in October 2012. We partner with all of the research institutions in New York City, and our principal supporter is the Robertson Foundation, which allows us to preserve the culture of the meeting. And a critical priority was to have a state-of-the-art, privately funded laboratory where you could check politics at the door and do the most advanced work. The laboratory has evolved from what was originally a small but important laboratory, to now one of the largest stem cell research laboratories out there. We have gone from 500 ft2 to many, many times that. From the start we have been doing very exciting work. This has created a vibrant community and we now have 45 researchers employed by NYSCF. When you have future science group
The New York Stem Cell Foundation
exciting work going on, it attracts more exciting work and more exciting people; consequently, the laboratory has grown hugely and become a much larger part of our program. The NYSCF laboratory has doubled in size three times since opening. What is it that attracts researchers to this laboratory? Scientists gravitate to where the top research is being done. Work from our laboratory has been cited three times in the last 5Â years as the top medical or scientific research breakthrough of the year. For example, last year our researchers successfully reprogrammed an adult skin cell into an embryonic stem cell through nuclear transfer. That has never been done before and was greeted with international acclaim, including being named the number one medical breakthrough by Time magazine. It is an extremely optimistic place. The main focus of research at NYSCF is on preclinical work: what was the rationale for that? You have to take a look at where the field is. If you donâ&#x20AC;&#x2122;t know where you are going, any road will take you there. So we think it is extremely important
future science group
to map out a plan for each one of the diseases where we are trying to accelerate treatments. However, we have already started doing translational work and as the field matures, you are going to see us move much more into translational work. For example, we are cooperating with Pete Coffey and the London Project to Cure Blindness, who are going to be starting clinical trials in patients with macular degeneration in the UK at the end of this year, with Pfizer. What do you see as the main challenges to translation of stem cells into regular clinical use? I think that is a question of time. If you look at how young this field is, compared to say bone marrow transplants, and also given the political scrutiny, I think that the field is doing extremely well. I think our challenge is to make sure that an excellent standard is maintained and that as people see an opportunity in this field we donâ&#x20AC;&#x2122;t end up with unproven therapies and stem cell tourism. That could be really detrimental to the field. But we are already seeing drugs that have been pre-screened using stem cell-derived disease models entering clinical trials,
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and I think we are going to see a real on rush on that. One of the things we are focusing on is the new technology that we have developed, the NYSCF Global Stem Cell Array, which industrializes the production of stem cell lines. This is going to be critical for moving to translation. Where does NYSCF plan to focus its efforts over the next 5 years? We see the NYSCF Research Institute as a key technology partner, to both academic researchers and industry, bridging that huge gap between what goes on in an academic research laboratory and the end goal of better, safer drugs and treatment, much sooner at much less cost.
Financial & competing interests disclosure The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
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Commentary Why the stem cell sector must engage with social media Lee Buckler* In 1995, I was a first-year associate in a downtown law firm excited to be invited to my first firm retreat. Undoubtedly because of my incessant whining on the matter, I was asked to present to the management committee the case for why the firm should have a website and perhaps even consider implementing email. It was not an easy sell. In the figurative blink of any eye (and literally within 3 years) websites and email were considered an absolute essential to even the most wrinkled partner with a dictaphone glued to their thumb. We are just barely beyond similar days in terms of social media acceptance. Social media is still considered by many to be a tool of frivolity, best limited to personal rather than business use, or perhaps at best only of real commercial utility in business-to-consumer applications. Certainly nothing could be further from the truth and in less than the blink it took for the commercial world to accept websites and email, it will seem similarly ridiculous for professionals, academics and companies to operate and succeed without actively using social media.
The case for social media engagement You may be thinking ‘I am a serious professional. I don’t need social media.’ You are wrong. Not only would your career benefit from your use of social media, your career needs it. Even as the most highly specialized and cloistered academic, if you are gleaning all of your information from paper publications (or even their digital versions), your information input is outdated and limited to such an extent that unless you have plans to retire in the next 5 years your career will suffer real consequences. In addition, if the extent of your networking is people you meet in real life, your career will lag behind those people building virtual networks. I can tell you without the slightest hesitation of conviction – having experienced it myself and seen it repeated countless times – active and successful social media engagement translates into: Unparalleled learning: accessing more information relevant to your
discipline, specialty and company than you otherwise will. Enhanced profile: higher profile within your industry, profession, specialty and community. Social media is not the only way to build a profile but it can be very effective; Wider network: more touch points and meaningful relationships with people than you otherwise will accomplish by any other means combined (Figure 1). If you do employ social media to enhance your knowledge base, increase your profile and establish influence over a wider network, is that all social media is about? Is it really just about a louder megaphone, a faster stream of incoming data and/or pandering to one’s ego? Here is the trick with social media. It enjoys irony. If you use it primarily to increase your profile, it will backfire. For those using social
*Author for correspondence: Lee Buckler, Cell Therapy Group. www.celltherapygroup.com
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media wrong, their megaphone and ego is not tolerated and it simply does not translate into more influence or a wider network. Think of what you say on social media as a conversation, not a message. It is an important pillar of marketing but it is not advertising; it is critical to communications but it is not a news feed. If you’re using social media like radio, you’re doing it wrong. It is a telephone. It involves listening, sharing and conversing. You will feel the pain if you try to have a one-sided conversation about yourself because not only will people ‘hang-up’ (unfollow), they will often penalize you for inappropriate behavior. Social networks do more than peer review, they peer punish. For those doing it right and reaping the three above-stated rewards, what are the real, measurable benefits for your career and organization or company?
Benefits for your career It is your company or organization. Even more importantly, it is your career. To optimize success, managing these now means managing them online.
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Traffic You can use social media to push and pull audiences to view your site, presentations, publications etc. For companies, increased traffic equals increased opportunity to call readers/viewers to your intended action – interaction, citation, linking, investing, buying or engaging in some other action you solicit. For individual professionals, increased viewers translate into more chances for collaboration, citation, engagement, etc. In a recent blog post, Deevy Bishop, Professor of Developmental Neuropsychology at Oxford, makes the case that search engine ranking and online accessibility now far outweigh journal impact factor as a key driver in how many times a paper is cited [1] . As Paul Knoepfler wrote in a comment for Nature News: “Savvy scientists must increasingly engage with blogs and social media… Even if you choose not to blog, you can certainly expect your papers and ideas will increasingly be blogged about. So there it is – blog or be blogged.” Collaboration There is an intrinsic correlation between one’s profile and the opportunities one has for collaboration. Increased positive profile all but assures
increased invitations to collaborate and/or more favorable responses from those with whom you ask to collaborate. For companies this means finding the right partnerships, joint ventures, strategic alliances, collaborators, employees, management and so on. For individual professionals, this means more and/or better quality invites to speak, write or collaborate in other ways. It also means finding quality grad students, faculty, employees and interns. Revenue/income This is about translating a broader knowledge base and a wider network over which you have some level of influence (if only just that they are listening) into more money for your company, organization and yourself. For companies, this means finding the right partners, investors, customers and so on. For organizations this means finding the right donors, impressing the right grant reviewers and/or recruiting the right rain-maker faculty. For individual professionals this translates into promotions or job offers. In a June 2012 blog post entitled ‘Why Scientists Should Publicize Their Findings – for Purely Selfish Reasons’ on the Scientific American Blog, Matt Shipman states: “There’s a reason that most grant proposals include a section asking how you plan to disseminate your findings. Most
federally funded agencies want the public to know about the work they are supporting. It helps give agencies the political support they need to get additional funding in the future… Obviously the work that you do under a grant is paramount, but doing a good job of publicizing that work will also stand you in good stead with the agencies. Yes, program officers notice” [2] .
Communicating your work to the public In a great five-part series earlier this year on the Scientific American blog called Social Media for Scientists, Christie Wilcox makes a compelling case for why scientists should and must engage in social media activity. She begins by making the case that science has an image problem – a lack of it and the wrong kind – and that if we are not largely to blame we are certainly guilty of not addressing it. “Only 18% of Americans can name a living scientist” she claims. “That statistic crushes my heart” [3] . She pinpoints the core problem as scientists failing to engage anyone other than their scientific peers in a discussion of what they are passionate about and do. “Right now, science is almost entirely a one-way conversation. Scientists, as a group, pride themselves on doing cuttingedge research and publishing it in the toptier journals of their field – then most feel that their part in the conversation is over.
Case studies Learning In a great blog post advocating Twitter for academics, Deevy Bishop, Professor of Developmental Neuropsychology at Oxford, states “When I first joined up I was impressed to find that within the first few days, I’d been directed to two new papers in my field that were very relevant to my work and that I hadn’t known about.” [1] Network Recent postdoc, Alexey Bresenev, blogger at StemCellAssays.com and CellTrials.info, directly attributes finding his current job to the contacts and impressions made as a result of his blogging efforts. With the San Diego Biotechnology Network (SDBN.org) Mary Canady, a biotechnology consultant (see Comprendia.com) in CA, USA has been successful in leveraging a LinkedIn group and website into a virtual networking organization (with over 7000 LinkedIn group members) that also holds outstanding, local, in-person educational and networking events. Influence Paul Knoepfler, associate professor at UC Davis and blogger at iPScell.com, is one of the few stem cell research professors regularly blogging. As such he is increasingly interviewed as a representative of the sector. His reputation as an academic unafraid to ask the unasked questions and engage in a fair and open discussion with both (or all) sides of an issue has opened up opportunities for him that he believes is undoubtedly benefiting his career.
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The problem is, these publications aren’t really communicating science to anyone but other scientists [4] .
Figure 1. Three main benefits of social media: unparalleled learning; enhanced influence and a wider network.
“In a way,” she continues, “the general public are our customers. Every day, we ask them to spend their time and money supporting science. We tell them what we do is vital, that they need to tell their representatives that science and science funding matter. We want their votes and their tax dollars and for them to take the time to understand the issues scientifically, but then we say we don’t have time to really interact with them? To walk them through what we do, why it’s cool, and get them excited about our research? [5] .
Learning
Influence
Using your influence to drive the field forward With a higher profile (wider network and influence) comes personal opportunity and benefit but also broader responsibility. You will be provided opportunity to leverage your profile to: Answer your profession’s critics;
Network
Be a voice for the voiceless; Inf luence policy, regulation and funding; Influence public perception; Ultimately, contribute to the progress of the field, which has real potential to help people.
Conclusion In February 2012, on AstraZeneca’s US business blog (AZ Health Connections), Tony Jewell posted the results of a survey they had conducted of their scientists and some of their partners around the world. A total of 57% of respondents said social media was ‘essential’, ‘very valuable’ or
you, your company/organization and your career will benefit from you engaging there too. As Wilcox summarizes:
‘valuable’ to their work. Over 60% of respondents said the primary value was in ‘information/collaboration’, ‘knowledge building’ and ‘networking’. Over 70% said they participated in social media professionally but most do so passively. Over 50% ‘read/watch’ but less than 20% ‘post comments’, ‘join discussions’ or ‘generate content’ [6] . In order to create the kinds of perceptions and solicit the kinds of actions we want from the world around us, we must engage the world around us. The world around us is engaging online. For all kinds of selfish and selfless reasons
“The ways in which new media can influence, improve, and revolutionize research are vast and continue to expand and evolve as quickly as the social media landscape” [7] .
Financial & competing interests disclosure The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
References
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1
Bishop D. How to bury your academic writing. Bishop’s blog. 26 August 2012.
2
Shipman M. Why scientists should publicize their findings – for purely selfish reasons. Scientific American blog. 18 June 2012.
3
Wilcox C. Social media for scientists part 1: it’s our job. Scientific American Blog. 27 September 2011.
5
Wilcox C. Social media for scientists part 3: win–win. Scientific American blog. 10 October 2011.
4
Wilcox C. Social media for scientists part 2: you do have time. Scientific American blog. 29 September 2011.
6
Jewell T. Survey: how our scientists use social media. AZHealthConnections.com. 12 February 2012.
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Wilcox C. Guest editorial: it’s time to e-volve. Taking responsibility for science communication in a digital age. Biol. Bull. 22285–22287 (April 2012).
Information Resources Buckler L. If you’re breathing, you’re in PR. Cell therapy blog. 11 June 2010. Small G. Time to Tweet. Nature 479, 141. 2 November 2011. Shipman M. A gentle introduction to
Twitter for the apprehensive academic. Scientific American blog. 14 June 2011. Buckler L. Don’t feel the pain of ignoring social media? Just wait a minute… CellTherapyBlog.com 22 October 2008. Bersenev A. Scientific blogging as a model for professional networking online. Cellular Therapy and Transplantation. 2(7), 10.3205/ctt-2010-en-000084.01 Bersenev A. Scientific blogging as a model for professional networking online. 4 August 2010. StemCellAssays.com
Bersenev A. Who’s who in the stem cell blogosophere. 27 June 2011. StemCellAssays.com Knoepfer P. Top ten tips for blogging for scientists. 2 August 2012. IPScell.com. The Rules of social media. Fast company. 8 August 2012. What is a scientific social network? 6 thriving and inspiring examples. 12 March 2012. Comprendia.com
Current Protocols in Stem Cell Biology EDITED BY: Thorsten Schlaeger (Editor in Chief), Roger Patient, Evan Snyder, Yukiko Yamashita, and Joseph Wu Published in affilication with the
International Society for Stem Cell Research (ISSCR)
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Article type
AROUND THE WORLD
global updates USA Kirstin RW Matthews & Maude L Rowland Canada Lisa Willemse, Ubaka Ogbogu, Stacey Johnson & Michael Rudnicki UK Emily Culme-Seymour Sweden Outi Hovatta Brazil Rosalia Mendez-Otero & Antonio Carlos Campos de Carvalho 10.2217/RME.XX.XX © 2011 Future Medicine Ltd
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AROUND THE WORLD
Global Update USA
After a tumultuous 2011 court battle over human embryonic stem cell research, this year US politics focused on the growing issues associated with unproven stem cell treatments. One prominent media topic was US professional athletes, such as Peyton Manning and Terrell Owens, seeking therapies abroad for various injuries [102,103] . In addition, the news outlets began to cover a pending FDA lawsuit against a Colorado company, Regenerative Sciences, Inc., for its use of mesenchymal stem cells to treat musculoskeletal and spinal injuries. The lawsuit will determine whether the FDA can oversee autologous adult stem cell treatments as a medical procedure or drug manufacturing [2] . Significant news coverage also surrounded Texas Governor and presidential candidate Rick Perry, who announced that he received stem cell injections while having back surgery in 2011 [3] . Afterwards the governor asked the Texas Medical Board to review its 126
Innovative company
Despite the political nature of stem cell research, this area of science continues to flourish in the USA. In 2011, the NIH funded approximately US$1.2 billion in stem cell research – a steady increase from past years – with US$123 million devoted to human embryonic stem cells [101] . According to the ISI Web of Science, more than 4000 USauthored stem cell publications were produced in 2011, accounting for approximately 38% of the world total. Approximately a quarter of these publications were collaborations with authors from other countries [1].
StemCells, Inc was founded with the mission “to realize the full potential of stem cells to transform medicine” with the goal to “discover, develop and commercialize breakthrough therapeutics” [105]. Based in Newark, California outside of San Francisco, the company supports research as well as clinical trials. It is currently sponsoring a Phase I/II trial for chronic spinal cord injury, a Phase I trial for Pelizaeus–Merzbacher Disease, and a Phase I trial for Neuronal Ceroid Lipofuscinosis (Batten Disease). Furthermore, StemCells has 25 publications related to its work dating back nearly 20 years, proving its research and therapies are grounded in solid scientific research.
California Institute for Regenerative Medicine
Key institution
Kirstin RW Matthews* & Maude L Rowland
StemCells, Inc.
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The California Institute for Regenerative Medicine (CIRM) was founded in 2004 after California voters approved a US$3 billion proposition to invest in stem cell research in 2003 [106]. Their mission is to “support and advance stem cell research and regenerative medicine.” Each year, CIRM awards grants to universities, institutions and companies for basic and applied research, facilities, training grants, and educational programs. To date, CIRM has awarded 519 awards for a total of US$1.4 billion to 65 institutions. In addition, CIRM has created 25,000 jobs and US$200 million in tax revenue. One of CIRM’s main agendas is to translate stem cell research to the clinic. To this end, it has now begun to invest more of its dollars in research with a therapeutic end goal.
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A strong supporter of stem cell research is The New York Stem Cell Foundation (NYSCF), which was founded in 2005 by business woman and entrepreneur Susan Solomon using her personal funds [107] . The mission of NYSCF ‘is to accelerate cures for the major diseases of our time through stem cell research.’ To accomplish this, it sponsors research at the foundation’s own laboratory facilities, awards grants to young investigators and funds postdoctoral fellowships. NYSCF also hosts symposia, conferences and workshops throughout the year. Even with its limited annual budget of approximately US$18 million, NYSCF has funded some of the field’s top researchers, including Peter Coffey, Kevin Eggan and Dieter Egli.
Aastrom Biosciences Aastrom Biosciences concentrates on cardiovascular disease using adult stem cells. Founded in 1989, its offices are headquartered in Ann Arbor, Michigan [108] . The company is sponsoring two clinical trials: Phase III (special protocol assessment) for critical limb ischemia and a Phase IIa (FDA orphan designation) for dilated cardiomyopathy. In addition, it has over 20 scientific peer-reviewed publications linking its research to the company’s trials.
NIH Center for R egenerative Medicine
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Innovative company
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The New York Stem Cell Foundation
The NIH is the major funder of stem cell research in the USA, giving more than US$1 billion in awards each fiscal year. To demonstrate its commitment to stem cell research and regenerative medicine, it established the Center for Regenerative Medicine (NIH-CRM) in 2011. Led by renowned stem cell researcher Mahendra Rao, the center aims to “provide the infrastructure to support and accelerate the clinical translation of stem cell-based technologies and … develop widely available resources to be used as standards in stem cell research” [109]. NIH-CRM funds intramural stem cell research across all of the institutes at NIH and maintains stocks of iPS cell lines and differentiated cell populations for distribution. In addition, NIH-CRM’s website provides an array of information to researchers from informed consent documents to protocols for differentiation processes.
Maude L Rowland, James A Baker III Institute for Public Policy, Rice University, 6100 Main Street, MS-40, Houston, TX, USA 77005 *Author for correspondence: Kirstin RW Matthews, James A Baker III Institute for Public Policy, Rice University, 6100 Main Street, MS-40, Houston, TX, USA 77005; Tel.: +1 713 348 4784; Fax: +1 713 348 5993; krwm@rice.edu
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Ones to watch... With hundreds of stem cell researchers in the USA, there are many young investigators who are doing groundbreaking work. This report highlights three individuals, from various subdisciplines, who have stood out this past year and could potentially be the future leaders in this field: Dieter Egli, Todd McDevitt and Melinda Fagan.
Dieter Egli Senior Research Fellow at The New York Stem Cell Foundation and Adjunct Associate Research Scientists in the Division of Molecular Genetics, Department of Pediatrics, Columbia University.
Education: PhD at University of Zu-
rich, Switzerland and postdoctoral training in the laboratory of Kevin Eggan at Harvard University. Research focus: Egli describes his focus as “the generation of therapeutically relevant cells for diabetes” [110] . He utilizes somatic cell nuclear transfer (SCNT) techniques to create donorspecific stem cells to be used to study disease, screen for new drugs, and cell replacement therapies. Key achievements:
He published the 2011 report in Nature describing the first modified human SCNT cells [5] . The technique inserted adult cell DNA into human oocytes allowing them to give rise to blastocysts and ultimately ESCs. Described as the “first – albeit genetically abnormal – human pluripotent stem cells” created through SCNT, the paper also highlights major technical barriers for the technique’s application to human cells [6] . Egli’s research involves paying women for their oocytes, which led to a series of commentaries on the topic, included a paper he first authored [6–8] . policy on autologous stem cell treatments after encouragement by his surgeon, Dr Stanley Jones, who co-founded the autologous stem cell therapy company, CellTex [4] . CellTex actively performs stem cell procedures, which have no clinically proven efficacy. 128
His Nature research was named the #1 medical breakthrough of 2011 by TIME magazine as well as landing him on its 2011 list of “People Who Mattered.” [111,112] . Todd McDevitt Associate Professor, Petit Faculty Fellow for the Institute for Bioengineering and Bioscience and Director of the Stem Cell Engineering Center at Georgia Institute of Technology.
Education: PhD in bioengineering at the University of Washington in 2001. Research focus: Engineering stem
cells into “effective cellular and molecular therapies for the treatment of degenerative disease and traumatic injuries.” [113] . Key achievements:
McDevitt was the 2010 recipient of the Young Investigator Award from the Society for Biomaterials [113] . He was co-prinicipal investigator for an NSF Integrated Graduate Education and Research Training grant funding a program in stem cell biomanufacturing, which was described by Nature as an “out of the box” opportunity for students interested in stem cell research [9] . McDevitt has published over 30 scientific articles and coauthored three book chapters.
Some stem cell researchers even believe these procedures should be prohibited by the FDA. Dr Jones claimed that the stem cell transplants were tissue transplants and, therefore, outside the reach of the FDA, similar to the argument being challenged in the FDA versus Regen. Med. (2012) 7(6 Suppl.)
Melinda Fagan Assistant Professor of Philosophy at Rice University
Education: PhD in biological sci-
ence from Stanford University (Irving Weissman lab) in 1998. PhD in history and philosophy of science from Indiana University, Bloomington in 2007. Research focus: the relationship between experimental practice, models and explanations. How is scientific knowledge related to experimental practice? How do (or should) social interactions and values impact scientific knowledge? What counts as scientific knowledge anyway – and on whose authority? [114] . Key achievements:
Fagan’s forthcoming book Philosophy of Stem Cell Biology: Knowledge in Flesh and Blood from Palgrave– Macmillan will examine stem cell biology from a philosophy of science perspective, emphasizing the i nter re l at ion of c onc ept s , experimental methods, model systems and evidential judgments. Fagan argues that philosophy of science can help stem cell researchers communicate the value and importance of their work to a broader audience, as well as insights on debates among scientists themselves. Over the past 5 years, Fagan has published over 20 articles related to philosophy of science and philosophy of biology. Regenerative Sciences case. In April 2012, the Texas Medical Board ultimately approved regulations stipulating only doctors can perform the procedures and requiring oversight by an institutional review board and compliance with state and federal regulations. future science group
USA
It remains to be seen if this policy is more or less stringent than current federal regulations. In addition, scientists have been divided on whether the Texas Medical Board decision benefitted or hurt regulation of unproven treatments [104] . Overall, it is unclear if these unproven treatments are actually benefiting patients. Several companies have been misleading in the efficacy and applicability of the therapies. But both the companies and patients have been averse to letting the FDA regulate or evaluate the procedures despite the fact that most scientists and ethicists have been supportive. Furthermore, stem cell scientists worry that a bad outcome could damage the public’s perception of stem cell therapy in general.
Acknowledgements The authors would like to acknowledge Rice student George Romar for his help in the preparation of this manuscript. Financial & competing interests disclosure Support for the authors was provided through the State of Qatar Endowment for International Stem
Cell Policy. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
Key strengths The US federal government strongly supports biomedical research, devoting over US$30 billion a year to the NIH, with over US$1 billion dedicated to stem cell research. NIH strongly encourages stem cell research and translational medicine, with the development of the new NIH-CRM and National Center for Advancing Translation Sciences that links academic scientists with industry. Academics are strong and vocal advocates for blocking unproven and unsafe stem cell treatments from being marketed in the USA.
References 1
2
Luo J, Flynn JM, Solnick RE, Ecklund EH, Matthews KRW. International Stem Cell Collaboration: how disparate policies between the United States and the United Kingdom impact research. PLoS ONE 6(3), e17684 (2011). Lysaght T, Campbell AV. Regulating autologous adult stem cells: the FDA steps up. Cell Stem Cell 9(5), 393–396 (2011).
9
Wadman M. Biomedical research: growing with the flow. Nature 474(7350), 241–243 (2011).
Websites 101 National Institutes of Health.
http://www.nih.gov 102 “Peyton Manning’s Stem Cell Hail Mary”,
Cyranoski D. Texas prepares to fight for stem cells: nature news. Nature 477(7365), 377–378 (2011).
4
Cyranoski D. Stem-cell therapy takes off in Texas. Nature 483(7387), 13–14 (2012).
103 “Report: Terrell Owens is in Korea for stem
5
Noggle S, Fung H-L, Gore A et al. Human oocytes reprogram somatic cells to a pluripotent state. Nature 478(7367), 70–75 (2011).
6
7
8
Daley GQ, Solbakk JH. Stem cells: triple genomes go far. Nature 478(7367), 40–41 (2011). Egli D, Chen AE, Saphier G et al. Impracticality of egg donor recruitment in the absence of compensation. Cell Stem Cell 9(4), 293–294 (2011). Hyun I. Moving human SCNT research forward ethically. Cell Stem Cell 9(4), 295–297 (2011).
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http://www.nyscf.org/about-us/our-mission 108 Aastrom Biosciences.
www.aastrom.com
ABC news-medical unit. http://abcnews.go.com/blogs/ health/2011/09/19/peyton-manningsstem-cell-hail-mary/
3
107 NYSCF.
cell treatment”, Yahoo! sports. http://sports.yahoo.com/nfl/blog/ shutdown_corner/post/report-terrellowens-is-in-korea-for-stem-celltreatment?urn=nfl,wp7544 104 Texas Register rule change for “Unlicensed
Practice”. http://www.sos.state.tx.us/texreg/archive/ March92012/PROPOSED/22. EXAMINING%20BOARDS.html#320 105 StemCells, Inc.
109 NIH-CRM.
http://crm.nih.gov 110 Dieter Egli.
http://nyscf.org/about-us/nyscf-team/ item/183-dieter-egli-phd-senior-researchfellow 111 TIME Top 10 medical breakthroughs: 1.
Scientists use cloning to create stem cells. http://www.time.com/time/specials/ packages/article/ 0,28804,2101344_21007 69_2100763,00.html 112 TIME Person of the year, people who
mattered. http://www.time.com/time/specials/ packages/article/0,28804,2101745_ 2102309_2102418,00.html 113 Todd McDevitt.
http://mcdevitt.gatech.edu/ 114 Melinda Bonner Fagan.
http://www.owlnet.rice.edu/~mbf2
www.stemcellsinc.com 106 CIRM.
http://www.cirm.ca.gov/
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AROUND THE WORLD
Global Update
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Canada
If Canadians have a global reputation for being ‘nice’, then our propensity for scientists to collaborate should come as no surprise. The Canadian stem cell and regenerative medicine field is particularly strong in terms of collaboration, research results and innovative programs to leverage investments in the sector. Canada continues to see significant achievements and changes that will have a broad impact on the ability to move translational research forward in the near future. One of the greatest strengths of the research conducted in Canada is its ability to break disciplinary boundaries and thus produce findings of incredible depth and breadth. Canada’s Stem Cell Network (SCN), a federally funded Centre of Excellence since 2001, has played a catalytic role in supporting crossdisciplinary research and in ensuring that a collaborative, networked community exists in Canada, despite obvious geographical challenges. An example of this collaboration is in the recent formation of the Till and McCulloch Meetings, which were held in Montréal, Québec in May 2012. Levering the success of earlier SCN scientific conferences, this event brought together several stem cell and regenerative medicine organizations from various regions across the country (pan-Canadian: SCN and Centre for Commercialization of Regenerative Medicine; provincial: Ontario Stem Cell Initiative and Québec’s ThéCell) for the largest scientific conference the 132
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Lisa Willemse*, Ubaka Ogbogu, Stacey Johnson & Michael Rudnicki
Institute of Biomaterials & Biomedical Engineering, University of Toronto The Institute of Biomaterials & Biomedical Engineering, located in the heart of Toronto’s Discovery District, is a multidisciplinary organization with a bioengineering focus that draws scientists and practitioners from applied science, engineering, medicine, dentistry and the life sciences. Research falls into the fields of neural and sensory systems; biomaterials, tissue engineering and regenerative medicine; nanotechnology and systems biology; and engineering in a clinical setting.
Terry Fox Research Institute Terry Fox Research Institute involves collaboration between cancer hospitals and research organizations across Canada, primarily in British Columbia, Alberta, Ontario and Québec. It currently supports translational programs with a focus on tumour site-specific research and cancer biomarkers.
Ubaka Ogbogu, University of Alberta, Edmonton, Alberta, Canada Stacey Johnson, Centre for Commercialization of Regenerative Medicine, Toronto, Ontario, Canada Michael Rudnicki, Stem Cell Network, Ottawa, Ontario, Canada *Author for correspondence: Lisa Willemse, Stem Cell Network, Ottawa, Ontario, Canada; lwillemse@stemcellnetwork.ca
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Northern Therapeutics is a biopharmaceutical company committed to the discovery and development of novel cell and gene therapies to extend and enhance the quality of the lives of people suffering from chronic life-threatening pulmonary disorders, in the absence of toxicity and major side effects. The company has developed a novel method for selective gene transfer and regenerative cell therapy targeting the pulmonary vasculature with the hope of repairing damaged lung tissues in a number of respiratory and cardiopulmonary conditions. Northern Therapeutics has offices in Montréal, Québec and Ottawa, Ontario, Canada.
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Innovative company
Northern Therapeutics
Institute for Research in Immunology and Cancer, University of Montréal The Institute for Research in Immunology and Cancer was one of the first research centers in Canada to adopt integrated systems biology as the core of its research model. Its 400 members use genomics, proteomics and bioinformatics to inform research in cancer, with a particular focus on clinical translation.
Innovative company
Octane Biotech
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Octane Biotech focuses on clinical systems for cell and tissue therapy. Octane’s vision is to deliver cell therapy and tissueengineered implants through turnkey automated processes, for example, interlinked bio reactors that provide precise control over the steps of cell source isolation, cell expansion, cell collection, cell washing, and final implant formation. Octane is based in Kingston, Ontario, Canada.
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country has yet to see. Owing to its success, planning for the 2013 Meetings are already underway, to be held 22–25 October in the mountain town of Banff, Alberta. Meanwhile, the SCN-secured its final tranche of funding, valued at close to CAN$20 million, in 2011. Following this, SCN announced investment in three global projects that are aimed at leveraging research in which Canada has substantial strength and capacity: drug discovery using cancer stem cells; neural and tissue repair using endogenous stem cells; and expansion of hematopoietic stem cells for clinical use. In January 2013, SCN will also announce new projects that will build on a growing cell therapy platform and bring together cGMP facilities from across the country in order to streamline efforts nationally. Formed in 2010, the Centre for Commercialization of Regenerative
Medicine, a not-for-profit network that supports the development of technologies that accelerate the commercialization of stem cells and biomaterials-based technologies and therapies, became one of an elite group of international regenerative medicine translation centers to join the Regenerative Medicine Coalition (RMC). The RMC, based out of Berlin, Germany, launched in May 2012. The aim of the RMC is to harness expertise to advance the field of regenerative medicine and to commercialize new discoveries. The RMC is being led by Frank-Roman Lauter of the Berlin–Brandenburg Center for Regenerative Therapies. In a year of celebration marking the 50th anniversary of the identification of stem cells by James Till and Ernest McCulloch, the Canadian Stem Cell Foundation recognized the achievement with a formal gala in Toronto, Ontario.
This was the first major event for the recently formed Foundation, which aims to serve as a champion for stem cell research in Canada, and, with the announcement of Dr Alan Bernstein as its Board Chair, is expected to become a major player in the upcoming years. Finally, policy changes were once again at the forefront of news in Canada. The federal government recently passed legislation that included amendments to the Assisted Human Reproduction Act, which governs embryo research, including many aspects of stem cell research. The amendments implemented a 2010 Supreme Court of Canada ruling that invalidated several provisions of the law on the basis that the power to enact those provisions belonged to the provinces. It also abolished Assisted Human Reproduction Canada, the federal agency charged with the responsibility of enforcing the legislation. Other
Ones to watch... With hundreds of stem cell researchers in the Canada, there are many young investigators who are doing groundbreaking work. This report highlights three individuals, from various subdisciplines, who have stood out this past year and could potentially be the future leaders in this field.
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Aaron Schimmer
Freda Miller
Timothy Kieffer
University Health Network, Toronto, Ontario, Canada
Hospital for Sick Children, Toronto, Ontario, Canada
University of British Columbia, Vancouver, British Columbia, Canada
Recent paper of note: Skrtic M, Sris-
kanthadevan S, Jhas B et al. Inhibition of mitochondrial translation as a therapeutic strategy for human acute myeloid leukemia. Cancer Cell 20(5), 674–688 (2011).
Recent paper of note: Wang J, Gallagher D, Devito LM et al. Metformin activates an atypical PKC-CBP pathway to promote neurogenesis and enhance spatial memory formation. Cell Stem Cell 11(1), 23–35 (2012).
Recent paper of note: Rezania A,
Research focus: chemical biology
Research focus: understanding how
and drug discovery with a focus on the apoptosis pathway. Screening of chemical and siRNA libraries to better understand biological pathways, apoptosis and the pathogenesis of leukemia, and to identify molecules that may serve as leads and prototypes for novel therapeutic agents for the treatment of leukemia and other malignancies.
growth factors in the neural environment regulate the genesis of neural cell types from embryonic neural stem cells and determine neuronal survival, growth, and ultimately connectivity. Her laboratory hopes that the lessons learned from studying neural development can be used to understand and potentially repair nervous system diseases and injury.
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Bruin JE, Riedel MJ et al. Maturation of human embryonic stem cellderived pancreatic progenitors into functional islets capable of treating pre-existing diabetes in mice. Diabetes 61(8), 2016–2029 (2012). Research focus: Cellular and physi-
ological studies of Type 1 and Type 2 diabetes, molecular therapeutics to modify cells in vitro to produce insulin or to expand pancreatic islet cells for transplantation. His team is also devising methods to encapsulate b-cells to protect them from immune rejection.
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changes include repeal of the licensing regime for research activities permitted by the legislation. However, aspects of the law that criminalize certain research activities, such as the creation of human embryos for research purposes, remain in force. Overall, the legislative changes will reduce regulatory overlaps and serve to improve the oversight of stem cell research in Canada.
Key strengths Highly collaborative culture across all research disciplines. Strong public support for stem cell research. 50 years of experience in the field; recognized world leader in hematopoietic and cancer stem cells Public healthcare system well suited to clinical trials.
Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
NASDAQ: STEM www.stemcellsinc.com
StemCells, Inc. is applying its scientific and industry leadership in stem cell biology to discover, develop and commercialize breakthrough therapeutics and enabling tools and technologies for research and drug discovery.
Credited with an impressive record of discoveries and firsts, the StemCells, Inc. team has a distinguished heritage of scientific achievement in stem cell biology. An unwavering commitment to rigorous science characterizes our culture, guiding our scientific and clinical integrity, as well as our business principles.
StemCells, Inc. is the first and only company to complete two US clinical trials using human neural stem cells, targeting central nervous system (CNS) disorders with our HuCNS-SC® product candidate. Our liver program is also among the first of its kind, targeting liver disease with our proprietary hLEC™ human liver engrafting cells.
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Global Update UK Emily J Culme-Seymour* 2012 has been an exciting year in the UK with substantial development on every front – research, clinical, industry and government. In particular, the focus has now moved to encompass far more post-research activities, with the continued enrolment of patients onto two pioneering Phase I clinical trials: ReNeuron’s ReN001 stem cell therapy for stroke (PISCES) in Southern General Hospital, Greater Glasgow and Advanced Cell Technology’s retinal pigment epithelial cells derived from human embryonic stem cells for Stargardts macular dystrophy and dry age-related macular degeneration at Moorfields Eye Hospital, London. The funding landscape for the sector has evolved from previous years to more fully embrace development and translation, including the provision of £180 million available for biomedical research via the Biomedical Catalyst Fund (joint Technology Strategy Board and Medical Research Council [MRC] funding) and a further £25 million through the UK Research Council’s UK Regenerative Medicine Platform initiative, as well as ongoing developments with the Cell Therapy Catapult, which all act to further encourage a pan-UK collaborative environment. Overall, the UK cell therapy community continues to thrive and impact heavily upon the worldwide sector, with an established research base, a solid approach to translation and a small but growing commercial sector that is going from strength to strength.
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Innovative company
Intercytex Intercytex is a cell therapy product and services company re-launched in November 2010, based in the Core Technology Facility in the University of Manchester Innovation Centre. The main focus of the company is developing their lead product ICX-RHY (VAVELTA®) to treat a variety of skin-related problems, including the severe genetic skin disorder epidermolysis bullosa, as well as for scar contractures. ICX-RHY is a suspension of human dermal fibroblasts in cell storage medium ready for injection into the skin. The company is currently involved in two clinical trials in the UK and the USA; one, a Phase II trial taking place in London using ICX-RHY to treat skin erosions in patients suffering from epidermolysis bullosa, and the other, a single-center Phase I/II study currently being performed in Pittsburgh, PA, USA, looking at the safety and efficacy of ICX-RHY to increase the joint mobility in patients suffering from dermal scar contractures.
Loughborough University Founded in 1996, Loughborough University has rapidly grown into one of the UK’s top universities, including world-leading cell therapy manufacturing activities. The Engineering and Physical Sciences Research Council Centre for Innovative Manufacturing in Regenerative Medicine was established at Loughborough in 2010 and is focused on translating ideas into treatments through pinpointing commercially robust practices and processes that can improve product development and manufacturing processes. The center is led by Professor David Williams, who brings his wealth of manufacturing know-how to direct world-class research and lead on a number of high-value projects, as well as linking up to other centers in the UK through a strong collaborative network.
Innovative company
Azellon Cell Therapeutics
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Azellon is focused on developing stem cell therapies for the repair of avascular meniscal tears. The technology behind Azellon was developed by cofounder Professor Anthony Hollander over the last 9 years and is based around an autologous stem cell-populated construct for implanting onto the site of a meniscal tear, appropriately named a ‘cell bandage’. A membrane containing adult stem cells harvested from the patient’s iliac crest is surgically inserted into the tear in the meniscus and, once in place, the newly implanted cells migrate between the implant and the original tissue, thus leading to strong, long-term repair. The technology has already been proven highly efficacious in an in vitro model and following the successful completion of a £0.65 million financing round in November 2011, it is now being taken into the clinic following regulatory go-ahead on a ten-patient Phase I/IIa trial, scheduled to begin in late 2012 at Southmead Hospital, Bristol, UK.
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The UK Stem Cell Foundation was founded in 2005 with the aim of accelerating stem cell translation from the laboratory bench to routine clinical practice. The Foundation has received endorsements from Government, the Medical Research Council, the Biotechnology and Biological Sciences Research Council and the Royal Society of Medicine together with twenty leading research universities, including Cambridge, Edinburgh, Imperial College, Manchester and University College London. The Foundation funds promising clinical projects in UK universities and hospitals and, to date, has dedicated over ÂŁ7.5 million to the sector. The UK Stem Cell Foundation is actively targeting the gap between discovery research and latestage clinical trials by funding and leveraging resources to support flagship UK projects, with the ultimate goal of achievement of new knowledge that has direct economic benefit to the UK.
Key institution
Innovative company
Key institution
UK Stem Cell Foundation
Cell Medica Cell Medica develops, manufactures and commercializes patient-specific cellular immunotherapy products comprised of antigen-specific T cells. The company was founded in 2006 by the current CEO, Gregg Sando, and has developed cell therapies for certain viral infections that follow a bone marrow transplant. The company is currently sponsoring two late-stage trials addressing the use of adoptive cellular therapy in treating cytomegalovirus infections, and plans a third study treating advenovirus infections. In addition, Cell Medica are developing a cell therapy using immune cells to recognize and kill malignant cells expressing Epsteinâ&#x20AC;&#x201C;Barr virus antigens, in collaboration with the Center for Cell and Gene Therapy at Baylor College of Medicine (TX, USA).
University College London As one of the worldâ&#x20AC;&#x2122;s top five universities and with grand challenge themes in both human wellbeing and global health, it is unsurprising that University College London (UCL), demonstrates world-class ability in the field of stem cell research, and it is probably now the global leader in clinical cell and gene therapy applications. The UCL Centre for Stem Cells and Regenerative Medicine, officially launched over 3 years ago, brings together 186 research groups from seven faculties, several specialized hospitals and a number of institutes. The UCL Cancer Institute, Institute of Neurology, Department of Hematology and the Advanced Centre for Biochemical Engineering are among the many UCL departments that are spearheading cutting edge stem cell, gene therapy and cell therapy research and development, and UCL is leading on translating discoveries into patient-ready therapies for the clinic within other departments, such as the Institute of Ophthalmology and the Ear Institute, as well as at the Royal Free Hospital and Great Ormond Street Hospital, all located in London.
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Ones to watch... Martin Birchall
Research focus: the principal focus
Chair of Larynogology at The Ear Institute within the Faculty of Brain Sciences, University College London.
is identifying molecules and signaling pathways that can be used to enhance repair in the damaged CNS in multiple sclerosis. Additionally, other ongoing collaborative projects in Charles’ laboratory address spinalcord injury and schizophrenia. The MRC Centre is based at the Scottish Centre for Regenerative Medicine Building, with new state-of-the-art facilities and a world-class team of scientists and clinicians. Sara Rankin
Research focus: led the European
team that successfully performed the world’s first stem-cell based, tissueengineered organ transplant in 2008 and has completed a number of airway replacements and laryngeal transplantations since. Martin has also assembled bespoke teams to address a variety of throat disorders, including the understanding of laryngeal immunity to help people with inflammatory (laryngitis) and malignant (throat cancer) conditions; repairing paralysed laryngeal nerves; and investigating viral (papillo matosis) and bacterial infections of the throat. Charles ffrench-Constant Director of the Medical Research Council Centre for Regenerative Medicine and Chair of Medical Neurology at the University of Edinburgh.
Professor of Leukocyte and Stem Cell Biology and Head of Regenerative Pharmacology group at the National Heart and Lung Institute, Imperial College London.
Research focus: focuses on understanding the impact of the bone marrow in inflammatory diseases and elucidating the molecular mechanisms regulating the exit of leukocytes and stem cells from the bone marrow.
Key strengths Robust UK government support and interaction, including commitment to research, translation and high value manufacturing of advanced therapies. Highly collaborative environment across the UK that transcends the traditionally perceived barriers between academia, clinical medicine and industry. Significant funding streams open to the cell and gene therapy sectors from multiple organisations, including Technology Strategy Board, Medical Research Council, Wellcome plus many other charities. Increasing focus on achieving clinical translation, including a network of five Academic Health Science Centers located across the UK that ensure partnerships between universities and healthcare providers, which focus on research, clinical services, education and training. A united industry voice through the BioIndustry Association Cell and Gene Therapy Industry Group which participates fully in UK and EU lobbying activities, inputs into government policy and represents the wider industry community to key stakeholders located in the UK and globally.
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Sara’s research output is being used to develop therapeutics that stimulate the activity of endogenous stem cells to promote tissue regeneration. Sara is also involved in a variety of public engagement and outreach activities. Fiona Watt Professor and Director of the Centre for Stem Cells & Regenerative Medicine at King’s College London (KCL).
Research focus: at the forefront of research into the use of stem cells in regenerative medicine and disease, with a particular interest in the development and renewal of skin stem cells. Fiona moved from the position of Deputy Director of the Cambridge Cancer Research-UK Institute at the University of Cambridge to found the new center at KCL in 2012. The Centre is planning to bring together the cutting-edge stem cell research currently taking place across KCL and its partner NHS trusts, as part of King’s Health Partners.
Financial & competing interests disclosure EJ Culme-Seymour is an investigator on the British Regen Industry Tool Set (BRITS) project funded by the Technology Strategy Board under their Regenerative Medicine Program: Value Systems and Business Modelling. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.
*Author for correspondence: Emily J Culme-Seymour, London Regenerative Medicine Network, 14a Clerkenwell Green, London EC1R 0DP, UK
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One small cell from man. One giant leap for science. Stem cells are a new frontier that hold great potential. But leaping from research to production presents a new set of challenges: consistency, reproducibility, efficiency and cost effectiveness. Our Mobius速 CellReady 3 L bioreactor is a convenient and cost-effective tool for the culture of clinical grade human mesenchymal stem cells (hMSCs). It is ready to use out of the box complete with protocols for transferring and optimizing your stem cell culture in a bioreactor format. Get out of this world results with the Mobius速 CellReady 3 L bioreactor. For more information on our stem cell program and the Mobius速 CellReady 3 L bioreactor, please visit www.emdmillipore.com/stemcells
EMD Millipore is a division of Merck KGaA, Darmstadt, Germany EMD Millipore and the M logo are trademarks of Merck KGaA, Darmstadt, Germany. Mobius is a registered trademark of Merck KGaA, Darmstadt, Germany. 息 2012 EMD Millipore Corporation, Billerica, MA USA. All rights reserved.
AROUND THE WORLD
Global Update Sweden Outi Hovatta* Swedish researchers have been very active in the stem cell field for many years. They have pioneered areas such as clinical treatment of Parkinson’s disease, developmental biology including early stem cells, human embryonic stem cells, induced pluripotent stem cells and human mesenchymal stem cells. The Swedish Research Council and other funding organizations have been very positive for stem cell research, and there is a favorable law in Sweden regulating human embryonic stem cell research. Many groups have been active partners in projects funded by the European Commission. Clinical trials are ongoing with mesenchymal stem cells in graft versus host disease and osteogenesis imperfecta. Successful transplantations of trachea using a tissue-engineered product with cells cultured into a scaffold have been made recently [1]. Optimizing the stem cell type for these constructs is ongoing.
Human mesenchymal stem cells Human mesenchymal stem cells have been for the first time used very successfully in treatment of severe graftversus-host reaction [3] and these clinical studies continue at an international level, coordinated by Professor Katarina LeBlanc.
Innovative company
Vitrolife
Innovative company
Human embryonic stem cell lines Human embryonic stem cell lines have been derived since 2002 by developing the quality of the cells to clinical grade. More than 50 hESC lines have been derived while revealing the signaling mechanisms regulating their pluripotency and growth. In 2011, Professors Karl Tryggvason and Outi Hovatta’s collaboration resulted in animal substance-free, feeder cellfree chemically defined conditions to establish clinical-grade human embryonic stem cell lines [2] .
Vitrolife [101] in Gothenburg is an established manufacturer of culture media and other products for in vitro fertilization, being one of the world leaders in this. It has now also widened its development and production to new defined stem cell culture and cryopreservation media.
Cellartis Cellartis in Gothenburg, recently fused with Cellectis [102] , has been acting in the stem cell area already for several years. The company is carrying out high-quality research and development work, more recently particularly in hepatocyte and cardiomyocyte differentiation [5]. Cellectis stem cells, a Business Unit of Cellectis Group (Alternext: ALCLS), is a premier provider of stem cell-derived products and technologies. It has recently launched a human-induced pluripotent stem cell-derived hepatocyte product, human-induced pluripotent stem cell-HEPTM. Pharmacologic testing kits using cardiomyocytes, hepatocytes and neural cells differentiated from pluripotent stem cells, combined with culture medium and culture systems, are the main commercial products of this company.
Key strengths Permissive culture and society with clear, nonrestrictive legislation of stem cell research. Relatively good research and development funding. Established stem cell research networks with international connections. Long tradition with Biotech companies. 140
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Biolamina Biolamina [103] in Stockholm has successfully made excellent matrices for different types of stem cells, including a fully xeno-free, feeder-free system for derivation of human embryonic stem cell lines from single biopsied blastomeres of human embryos. The company manufactures all human laminins in human cells cultures, and it has a GMP-grade production facility for clinical-grade cells. It also produces kit of chemically defined matrices and chemically defined culture media for clinical-grade cells. Biolamina’s products have made cultures of human pluripotent stem cells very simple, comparable to other cell types, fibroblasts for example.
Karolinska Institutet Karolinska Institutet is a university that has wide stem cell research activities within collaborating centers. Different aspects of neural stem cells, from development to therapies have been studied at high impact level. Professor Jonas Frisen’s group has been productive in identifying mechanism of how the adult brain repairs itself [6] . There are many other outstanding neuroscientists based at the Karolinska Institutet.
Key institution
Key institution
Innovative company
Sweden
The University of Lund The University of Lund has an outstanding Stem Cell Center, with treatment of neurodegenerative disorders, particularly Parkinson’s disease and stroke, a strong focus [4,7]. Endodermal lineages and possible stem cell therapy for diabetes have also been active research topics in Lund [8].
*Author for correspondence: Outi Hovatta, Karolinska Institutet, Karolinska University Hospital Huddinge, K57, SE 141 86 Stockholm, Sweden; Tel.: + 46 8585 83858; outi.hovatta@ki.se
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Hovatta
Ones to watch... There are so many promising young stem cell scientists is Sweden, that it almost impossible to name just a few of them. Dr Malin Parmar from Lund University is a very promising scientist developing cell therapy for Parkinson’s disease [4]. Kirsty Spalding, from Jonas Frisen’s team, now independent, is another Swedish scientist excelling in the field of stem cell research.
Malin Parmar PhD, Associate Professor at Wallenberg Neuroscience Center, Developmental Neurobiology at Lund University, Sweden
Research focus: Malin Parmar has
been focusing on the development of neurons from human embryonic and induced pluripotent stem cells, with generation of chemically defined methods for differentiating dopamine neurons. Such cells can probably be used for clinical treatment in the future. She has received a highly competed European Research Council (ERC) grant in 2012. Selected publication: Kirkeby A,
Grealish S, Wolf DA et al. Generation of regionally specified neural pro-
Her primary interest is in investigating the origin and turnover of adipocytes, their progenitor cells and lipid stores in lean and obese individuals, after a most productive postdoc period in professor Jonas Frisen’s group.
a cluster referred to as the metabolic syndrome. Therefore, Kirsty Spalding has been recently studying lipid turnover and cell age are studied using radiocarbon dating. By studying cell turnover in a variety of different adipose depots (such as various subcutaneous adipose depots as well as visceral depots) we aim to better understand the regulation of the fat mass in humans. Understanding the dynamics of adipocyte turnover may shed new light on potential treatments for obesity.
Research focus: her topic, obesity, constitutes a public health problem by enhancing the risk for diseases such as diabetes, fatty liver disease and atherosclerosis. Together these diseases form
Selected publication: Arner P, Bernard S, Salehpour M et al. Dynamics of human adipose lipid turnover in health and metabolic disease. Nature 478(7367), 110–113 (2011).
genitors and functional neurons from human embryonic stem cells under defined conditions. Cell Reports 1(6), 703–714 (2012). Kirsty Spalding PhD, Assistant Professor in Karolinska Institute, Sweden
Financial & competing interests disclosure The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
References 1
Jungebluth P, Alici E, Baiguera S et al. Tracheobronchial transplantation with a stem-cell-seeded bioartificial nanocomposite: a proof-of-concept study. Lancet 378(9808), 1997–2004 (2011).
2
Rodin S, Domogatskaya A, Chien K et al. Self-renewal of human embryonic stem cells on human recombinant laminin-511 in chemically defined xeno-free medium and environment. Nat. Biotechnol. 28(6), 611–615 (2010).
3
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Ringden O, Uzunel M, Rasmusson I et al. Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease. Transplantation 81(10), 1390–1397 (2006).
4
Parmar M, Björklund A. Generation of transplantable striatal projection neurons from human ESCs. Cell Stem Cell 10(4), 349–350 (2012).
5
Sartipy P, Björquist P. Concise review: human pluripotent stem cell-based models for cardiac and hepatic toxicity assessment. Stem Cells 29(5), 744–748 (2011).
6
7
Göritz C, Frisén J. Neural stem cells and neurogenesis in the adult. Cell Stem Cell 10(6), 657–659 (2012). Lindvall O. Why is it taking so long to develop clinically competitive stem cell therapies for CNS disorders? Cell Stem Cell 10(6), 660–662 (2012).
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8
Ameri J, Ståhlberg A, Pedersen J et al. FGF2 specifies hESC-derived definitive endoderm into foregut/midgut cell lineages in a concentration-dependent manner. Stem Cells 28(1), 45–56 (2010).
Websites 101 Vitrolife.
www.vitrolife.com 102 Cellectis.
www.cellectis.com 103 Biolamina.
www.biolamina.com
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AROUND THE WORLD
Global update Brazil Excellion & CellPraxys
Analysis of scientific activity in the field shows that publications from Brazilian scientists have increased steadily from nine publications in 2000 to 152 in 2011. Although extremely significant, this growth still puts Brazil in a modest 19th place in comparison to other countries in stem cell research. International cooperation also needs to be improved, since the great majority of the publications coming out of Brazil are authored only by Brazilian scientists. It is hoped that a recent binational program sponsored by the Argentinian and Brazilian governments may lead to more international collaboration. Another important initiative was the signing of a Memorandum of Understanding between the Brazilian National Research Council (CNPq) and the California Institute for Regenerative Medicine (CIRM) in 2012. In October, CIRM and the Brazilian Network for Cell Therapy (RNTC) [101] will hold a workshop involving 30 scientists from Brazil, Argentina and California (USA) to d iscuss possible collaborations.
This network (RNTC) involves eight Cell Technology Centers (CTCs) and 52 research laboratories financed through Requests for Application sponsored by the Ministry of Health and the Ministry of Science and Technology. The eight CTCs have the mission of producing clinical-grade stem cells (manufactured under c-GMP conditions) to be used in current and future clinical trials. Distributed throughout the country the CTCs are working to produce human embryonic and induced pluripotent stem cells, mesenchymal stem cells of diverse origins (e.g., bone marrow, adipose tissue, neonatal tissues), cardiac and neural stem cells. The 52 laboratories that are supported by the Request for Application are conducting basic (15 projects), preclinical (33 projects) and clinical research (four projects). These projects concentrate on the nervous and cardiovascular systems, but contemplate most physiologic systems. Brazil has achieved international recognition by the clinical trials performed in the country using cell therapies. In
Two companies are offering cell therapy services in Rio de Janeiro – Excellion offers cultured fibroblasts for rejuvenation and CellPraxys offers chondrocytes for cartilage lesions. CellPraxys is attempting to license a product for therapy of refractory angina.
Universidade de Sao Paulo
Key institution
Research using human embryonic stem cells (hESCs) was debated for 4 years in the Brazilian Supreme Court before being legally approved in 2008. Before that, only research with adult stem cells was supported by federal funding. Even with the ban on hESC research until 2008 the country made significant advances in stem cell research in the last decade [1]. Right after legislation permitted, the first Brazilian hESC line was derived, still in 2008 [2]. Achievements in the field were supported by policies directed to provide federal funding for stem cell research by the Ministry of Health. Investments since 2005 have mounted to over US$50 million, financing 110 projects, ranging from basic to clinical research.
Innovative companies
Rosalia Mendez-Otero* & Antonio Carlos Campos de Carvalho
This is the largest state university in the country and together with The Federal University of Rio de Janeiro is responsible for most of the research in stem cells. The university houses several groups under the leadership of professors or young investigators. The group coordinated by Dr Lygia da Veiga Pereira was responsible for the establishment of the Brazilian human embryonic cell lines (from blastocyst donated by Brazilians).
Antonio Carlos Campos de Carvalho, Professor of Physiology and Biophysics, Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Brazil; acarlos@biof.ufrj.br *Author for correspondence: Rosalia Mendez-Otero, Professor of Physiology and Biophysics, Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Brazil; Tel.: +55 212 562 6554; rmotero@biof.ufrj.br
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Key institution
Brazil
Fiocruz and Hospital Sao Rafael The Fundação Fiocruz and the Hospital São Rafael in Bahia, Brazil (in the northeast) are Institutions that have contributed importantly to the development of research groups in stem cells in the northeast part of the country. Fundação Fiocruz is a research institution of the Ministry of Health while the Hospital São Rafael is a nonprofit organization. The Bahia institutions have pioneered both animal studies and clinical trials in Chagas disease, in cirrhosis and more recently in spinal cord injury.
Key institution
Key institution
Universidade Federal do Rio de Janeiro
Pontificia Universidade Católica do Parana The Pontificia Universidade Católica do Parana is located in the south region of Brazil and has contributed importantly to the development of stem cell therapies in Brazil, notably for cardiac ischemic diseases. Under the leadership of Dr Paulo Brofman, a cardiac surgeon, the group has played an important role in preclinical and clinical studies in heart diseases.
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The Universidade Federal do Rio de Janeiro (Rio de Janeiro, Brazil) is the largest public federal university in the country and houses several research groups that are involved with stem cell research. The research areas range from human embryonic stem cells and human induced pluripotent stem cells to preclinical studies and clinical trials with adult stem cells. One of the interesting aspects of this institution is the close interaction among the groups working in the basic science departments and the clinical departments at the University Hospital. Several Phase I clinical studies using adult stem cells were concluded or were coordinated by the research groups at this university [13]. Many of these studies were multicenter studies conducted in several hospitals, such as the Instituto Nacional the Cardiologia, an institution of the Ministry of Health located in Rio de Janeiro which coordinated the Phase II/III study in cardiac diseases [14]. This was the largest study in the country in stem cell therapy.
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Mendez-Otero & Campos de Carvalho
Ones to watch... With hundreds of stem cell researchers in Brazil, there are many young investigators who are doing groundbreaking work. This report highlights three individuals, from various subdisciplines, who have stood out this past year and could potentially be the future leaders in this field.
Lygia da Veiga Pereira
Stevens Kastrup Rehen
Gabriel Rodriguez de Freitas
Professor at the Biology Institute of the University of São Paulo.
Professor at the Biomedical Institute of the Federal University of Rio de Janeiro.
Visiting Professor at the Instituto de Biofisica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro.
Education: Biology at the Federal University of Rio de Janeiro, PhD in the same University (2000).
Education: Medical doctor at Univer-
Education: Physics at the Catholic University in Rio de Janeiro; PhD at the Mount Sinai Graduate School – 1994. Research focus: embryonic stem cells
and induced pluripotent stem cells.
and induced pluripotent stem cells
Key achievements:
Key achievements:
Derived the first Brazilian human embryonic stem cell line in 2008
Derived induced pluripotent stem cell from schizopshrenic patients
Participated in the International Stem Cell Initiative
Generated a defined media for pluripotent cell culturing
Proposes to establish an induced pluripotent stem cell ba nk representing the Brazilian ethnic population
Maintains a blog and a highly visited page for public information about stem cells
auto immune diseases, research conducted by Brazilian groups has been prominent [3] . Two influential articles published in the Journal of the American Medical Association described autologous bone marrow transplantation in Type I diabetes [4,5] . The cardiovascular area has also seen major contributions from Brazilian institutions targeting four distinct cardiopathies [6,7] . Of note, the recent publication of an efficacy trial using bone marrow-derived cells in the setting of Chagasic cardiomyopathy [8] . Last, but not least, the pioneering trial using bone marrow-derived cells in ischemic stroke [9–12] , which demonstrated a satisfactory safety profile that led to the financing of an efficacy trial (to be started this year) in the aforementioned Brazil–Argentina cell therapy program. Brazilian research activity is highly concentrated in the southeast region, despite efforts by the Federal Government to change this picture in recent 146
Research focus: embryonic stem cells
decades. São Paulo, Rio de Janeiro and Minas Gerais States account for more than 70% of all research in this country. Stem cell research follows the pattern but there are exceptions. However, most of the knowledge produced in Brazil in the stem cell and cell therapy field is generated in two public universities of Rio and São Paulo. The Federal Uni-
sidade Federal Fluminense, PhD at the Universidade Federal do Rio de Janeiro (2004). Research focus: cell therapy in stroke
patients Key achievements:
Coordinated the safety study using bone marrow-derived stem cells in stroke patients Coordinates the efficacy study in stroke patients planned to start this year
versity of Rio de Janeiro (Universidade Federal do Rio de Janeiro) and the State University of São Paulo (Universidade de São Paulo) concentrate the largest number of research groups working in basic, preclinical aspects of stem cell research in the country. Institutes directly affiliated to the Ministry of Health in Rio de Janeiro, have also been promi-
Key strengths Continued support by the Ministry of Health, which considers stem cells and cell therapies as an important area for the public health system in Brazil. Highly motivated and dedicated students – from undergraduate all the way to post-doctoral fellows – interested in stem cells and cell therapies. A prominent role of Brazilian Institutions and medical researchers in developing clinical trials using cell therapies under strict regulatory and ethical standards. The need to increase the incipient participation of private companies in the area.
Regen. Med. (2012) 7(6 Suppl.)
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Brazil
nent in conducting clinical trials of cell therapy in cardiac diseases (National Cardiology Institute) and in bone and cartilage defects (National Trauma and Orthopedic Institute)
private sector has not been very active and there are few companies doing entrepeneurial activities in this field. Most of them are associated with cord blood banks and a few are spin-offs associated with academia.
Private companies The pharma and biotech sectors in Brazil are clearly under-represented in comparison to the size of the country’s economy. Following the trend, the
Besides Excellion and CellPraxys another private company investing in research and development has focused on developing reagents for stem cells is Hygeia, a spinoff from UFRJ.
Financial & competing interests disclosure The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.
References 1
2
3
4
5
6
bone marrow mononuclear cell transplantation through intracoronary injection post acute myocardium infarction – MiHeart/AMI study. Trials 9, 41 (2008).
McMahon DS, Singer PA, Daar AS, Thorsteinsdóttir H. Regenerative medicine in Brazil: small but innovative. Regen. Med. 5(6), 863–876 (2010). Fraga AM, Sukoyan M, Rajan P et al. Establishment of a Brazilian line of human embryonic stem cells in defined medium: implications for cell therapy in an ethnically diverse population. Cell Transplant. 20(3), 431–440 (2011).
7
8
Burt RK, Loh Y, Cohen B et al. Autologous non-myeloablative haemopoietic stem cell transplantation in relapsing–remitting multiple sclerosis: a Phase I/II study. Lancet Neurol. 8(3), 244–253 (2009). Voltarelli JC, Couri CE, Stracieri AB et al. Autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed Type 1 diabetes mellitus. JAMA 297(14), 1568–1576 (2007). Couri CE, Oliveira MC, Stracieri AB et al. C-peptide levels and insulin independence following autologous nonmyeloablative hematopoietic stem cell transplantation in newly diagnosed Type 1 diabetes mellitus. JAMA 301(15), 1573–1579 (2009). Dohmann HF, Silva SA, Sousa AL et al. Multicenter double blind trial of autologous
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9
Perin EC, Dohmann HF, Borojevic R et al. Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischemic heart failure. Circulation 107(18), 2294–2302 (2003). Ribeiro Dos Santos R, Rassi S, Feitosa G et al. Chagas Arm of the MiHeart Study Investigators. Cell therapy in Chagas cardiomyopathy (Chagas arm of the multicenter randomized trial of cell therapy in cardiopathies study): a multicenter randomized trial. Circulation 125(20), 2454–2461 (2012). Barbosa da Fonseca LM, Battistella V, de Freitas GR et al. Early tissue distribution of bone marrow mononuclear cells after intra-arterial delivery in a patient with chronic stroke. Circulation 120(6), 539–541 (2009).
10 Battistella V, de Freitas GR, da Fonseca LM
et al. Safety of autologous bone marrow mononuclear cell transplantation in patients with nonacute ischemic stroke. Regen. Med. 6(1), 45–52 (2011).
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11 Barbosa da Fonseca LM, Gutfilen B,
Rosado de Castro PH et al. Migration and homing of bone-marrow mononuclear cells in chronic ischemic stroke after intraarterial injection. Exp. Neurol. 221(1), 122–128 (2010). 12 Friedrich MA, Martins MP, Araújo MD
et al. Intra-arterial infusion of autologous bone marrow mononuclear cells in patients with moderate to severe middle cerebral artery acute ischemic stroke. Cell Transplant. 21(Suppl. 1), S13–S21(2012). 13 Couto BG, Goldenberg RC, da Fonseca
LM et al. Bone marrow mononuclear cell therapy for patients with cirrhosis: a Phase 1 study. Liver Int. 31(3), 391–400 (2011). 14 Tura BR, Martino HF, Gowdak LH, dos
Santos RR et al. Multicenter randomized trial of cell therapy in cardiopathies – MiHeart Study. Trials 8, 2 (2007).
Website 101 Brazilian Network for Cell Therapy (Rede
Nacional de Terapia Celular [RNTC]) www.rntc.org.br
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Karolinska Institutet A medical university Karolinska Institutet is one of the worldâ&#x20AC;&#x2122;s leading medical universities. Its mission is to contribute to the improvement of human health through research and education. Karolinska Institutet accounts for over 40 per cent of the medical academic research conducted in Sweden and offers the country´s broadest range of education in medicine and health sciences. Since 1901 the Nobel Assembly at Karolinska Institutet has selected the Nobel laureates in Physiology or Medicine. Visit us at ki.se
Continue the Journey Join us for the next World Stem Cell Summit December 4 – 6, 2013
San Diego, California Build on the momentum. Capitalize on your Summit experience. Distill and incorporate what emerged, and further explore what may be ahead. Follow-up with colleagues. And make plans now to continue the dialogue at the 2013 World Stem Cell Summit. Help grow the field. Demonstrate your commitment to the growth and success of regenerative medicine. Add your voice and impact to developments – and to solutions – through participation and advocacy. Amplify your efforts by encouraging colleagues and organizations to join you at the 2013 Summit. Together we’ll make a difference. Plan now. Take advantage of early registration discounts. Secure the best arrangements. Receive advance notices of speakers, agendas and news. Sign up for the 2013 World Stem Cell Summit today and continue the journey.
Save the Date: December 4-6, 2013 www.worldstemcellsummit.com
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