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Stem cells a clinical update Contact Information For all general enquiries please call our Customer Support team on: +44 (0) 1273 234 676
Prepared for: Healthcare and Medical Professionals
Alternatively please e-mail us on: technical@cells4life.com enquiry@cells4life.com Address: Cells4Life Ltd Sales & Marketing Division Sussex Innovation Centre Science Park Square Falmer Brighton BN1 9SB www.cells4life.com
www.cells4life.com
Prepared by: Rebecca Rutter BSc. Hons | Operations Manager Richard M Donavan BSc (Hons) MSc LIBMS | Laboratory Manager
2009
Index Page 3
Overview.
4
A Brief History of Stem Cells.
5
What is a Stem Cell?
7
Umbilicle Cord Blood (UCB) Stem Cells and Regenerative Medicine.
8
UCB, Cancer and Leukaemia. UCB, Cardiac Research and Therapeutics.
9
UCB, Huntington’s, Alzheimer’s and Parkinson’s. UCB, Stroke and other Neurological Injuries and Conditions.
10
UCB and Haematological Diseases and Disorders.
11
UCB, Bone and Osteogenic Diseases and Conditions. UCB, Ocular and Diseases and Conditions of the Eyes. UCB and Liver Disease. UCB and Autoimmune Diseases.
12
General Overview.
13
Diseases and Conditions in Focus.
14
The Law and Stem Cells (United Kingdom)
14
History.
15
Third Party Agreements. What you should do.
16
Overcoming Current Limitaions.
17
Cells4Life - Setting an Example.
18
The Future.
19
Glossary.
20
References.
Stem cells - a clinical update
Overview ‘Stem Cells – A Clinical Update 2009’ is a working document written and produced by the Medical Scientists working at Cells4Life. It is intended to provide the reader with an overview of the most up-to-date legislation and the clinical and therapeutic applications of umbilical cord blood (UCB). All the technical staff working at Cells4Life are dedicated UCB stem cell specialists and as the leading private UCB storage company in the UK, we are acutely aware of the questions and queries posed to us by patients, healthcare professionals and the public. This document should be able to provide the answers. Ultimately, the aim of this document is present information on:
• UCB as a valid source of stem cells • The use and limitations of stem cells • The role of UCB in regenerative medicine • Areas of research and clinical trials • Up-to-date legislation • Overcoming problems • The future At Cells4Life we are well aware that the process of deciding to store a child’s UCB for future potential therapeutic use can be a confusing one. Factors such as deciding on whether to store and/or donate to a public or private bank, which company to use and cost can all influence ones decision. With the help and guidance of knowledgeable and impartial healthcare professionals the process can in fact, be one of the easiest and best decisions you’ll ever make. Stem cell research is one of the fastest moving fields in medicine and the number of disciplines turning to stem cells as a source of treatment is rapidly increasing. At the 3rd World Congress of Regenerative Medicine Conference 2007 held in Leipzig, Germany it was noted by the Chair of the European Society of Organ Transplant (ESOT) that stem cells were the realistic option for a known field where demand far outstrips supply. All the information set forth in this document comes from peer-reviewed academic and scientific press (journals) and reputable sources, all of which are publically available for review.
Stem cells - a clinical update
A Brief History of Stem Cells In the early years of the twentieth century European scientists discovered that all the various types of blood cells in the body (red blood cells, white blood cells etc) all began life as one particular type of ‘stem cell’ before differentiating and becoming a specialised type of cell. These stem cells are now known as ‘haemopoietic stem cells’ (‘haemopoietic’ meaning ‘pertaining to the blood’). However, it wasn’t until 1963 that the first quantitative descriptions of the self-renewing activities of transplanted mouse bone marrow (BM) stem cells were first documented. As a result of these remarkable properties, scientists realised the potential benefits of stem cells and stem cell therapy. In the last fifty years, this realisation has materialised into countless successful stem cell based therapies for a number of haematologic, metabolic, oncologic and genetic diseases. Outlined below is a brief timeline of significant events in the history of stem cells. 1959 – First animals created by in-vitro fertilisation (IVF) 1968 – Discovery of haemopoietic stem cells 1978 – Stem cells first discovered in human umbilical cord blood 1981 – First in-vitro stem cell line developed from mice 1988 – Embryonic stem cell lines created from a hamster 1993 – First unrelated cord blood transplant 1995 – First embryonic stem cell line derived from a primate 1997 – First lamb cloned from stem cells 1998 – First human embryonic stem cell lines created 2001 – Focus on human embryonic stem cells and umbilical cord blood stem cells 2005 – Researchers in the UK develop cord blood-derived embryonic-like stem cells Within the human body, there are various sources of haemopoietic stem cells which include umbilical cord blood, bone marrow, peripheral blood and amniotic fluid and membranes. While harvesting stem cells from the bone marrow has long been traditional, this method is now becoming outdated as it is invasive can be very painful and for a number of reasons create ethical, moral and racial problems for the recipient. As newer sources of stem cells have been discovered, such as umbilical cord blood (UCB), the majority of these issues are no longer a problem. UCB is a rich source of stem cells and the collection of UCB is painless, non-invasive and simple. Furthermore, it raises no ethical or moral debate. The first successful use of UCB stem cells was in 1988 when a child from the United States with Fanconi’s anaemia (a rare form of aplastic anaemia) was treated with their siblings UCB (Gluckman et al, 1989). The recipient of the transplant remains alive and well today. More than twenty years later, even greater success is still being seen with UCB having been used in over 6000 transplants to date. It is now widely recognised that UCB is the mainstay of many transplants around the world. In recent years with even greater success, UCB transplants have come into their own as therapeutic options for a variety of diseases and conditions. In late 2007, a three-year old girl from New York in the USA was diagnosed with acute lymphoblastic leukaemia and treated with her own UCB stem cells. The rationale for storing the sample and the methods used were virtually identical to that of Cells4Life. After 20 months, the girl is in complete remission of the disease and is doing well (Hayani et al, 2007). More recently still, a case report published in the Chinese Medical Journal reports the case of a 15-month old girl diagnosed with malignant infantile osteoporosis (MIOP) who was treated with an allogenic UCB transplant and is now doing extremely well with the disease in total remission after 4 months of therapy (Tang-Her et al, 2008). Due to the undeniable life-saving potential of stem cells, stem cell research is one of the biggest areas of modern medical science. Currently, over 2000 articles per year based on stem cell research are published in reputable scientific journals. With breakthroughs being announced on an almost daily basis, stem cell therapy is becoming commonplace. The possibilities for stem cell research are truly endless, and yet unpredictable. If scientists can master the complex biochemistry behind stem cell development, stem cell technology could be used to produce replacement organs and to repair defective tissues/organs that have been damaged or destroyed by many of the most devastating diseases and disabilities.
Stem cells - a clinical update
What is a Stem Cell? As scientists discover more and more about stem cells, the exact definition of a stem cell can be a little confusing, and every stem cell scientist will probably give you a different answer were you to ask them! Essentially, a stem cell is a type of cell in the body which possess the following traits:
• The most primitive cell type • They are found in most, if not all, multi-cellular organisms • Capable of self-renewal through mitosis • They are undifferentiated • Can give rise to specialised cell types Stem cells have two important characteristics that differentiate them from every other cell type in the body – firstly, they are unspecialised cells that can renew themselves over long periods of time via a process called mitosis. One fundamental property is that they have no tissue-specific structures that allow them to perform specific functions. Secondly, under certain physiological conditions, stem cells can be induced to become other cell types with speacialised functions such as heart muscle cells or insulin-producing cells of the pancreas. When a cell replicates itself many times it is said to ‘proliferate’. A population of stem cells that proliferates for many months in a laboratory can yield millions of cells. If the resulting cells remain unspecialised, the cells are said to be capable of long-term renewal. Categorisation of stem cells is in fact rather complex so for simplicity, stem cells can be thought of as being in three different groups, all capable of doing something ‘different’. Pluripotent stem cell (PSC) These are the true stem cells, with the potential to make any of the differentiated cells in the body. Three types of PSC have been found - embryonic stem cell (ESC), embryonic germ cell (EGC) and embryonic carcinoma cells (ECC). Totipotent stem cell (TSC) This type of stem cell is called totipotent (‘toti’ being Latin for ‘whole’ or ‘total’) as it has the potential to become ANY other type of cell in the body, including those that make up the cells of the extra-embryonic membranes (i.e. the placenta) Multipotent stem cell (MSC) These are also true stem cells but unlike the types of stem cells, can only differentiate into a limited number of different cell types. The availability of cord blood as an alternative to bone marrow as a source of haematopoietic stem cells (HSC) for both autologous and allogenic transplantation has a number of potential advantages for both adults and children in clinical practice. These advantages include:
Stem cells - a clinical update
• Faster availability – patients on average receive cord blood transplants (CBT) earlier than those receiving conventional BM grafts
• Extension of the donor pool – CBT will tolerate a mismatch of tissue types between donor and recipient greater than is acceptable with BM or peripheral blood
• Because of the ethnic diversity of cord blood donors, there is a higher frequency of non-Caucasian HLA haplotypes available compared with BM registries
• Lower incidence and severity of graft versus host disease (GvHD) • Lower incidence of viral transmission, particularly cytomegalovirus (CMV) and Epstein-Barr virus (EBV) • Lack of donor attrition – BM donors may change their mind or become unavailable over time
Figure 1 – Differentiation of Stem Cells in Haemopoietic Cells
Image copyright of LifeEthics.org (2008)
Stem cells - a clinical update
Umbilical Cord Blood (UCB) Stem Cells and Regenerative Medicine Stem cell biology and regenerative medicine represent a new frontier for the scientists and doctors at the forefront of modern healthcare. In the last decade, attempts have been made with great success at treating a wide range of the most common diseases and conditions affecting human health. Clinical trials using autologous and non-autologous stem cells from a variety of sources are increasing. Various media outlets (broadsheet newspapers, TV, radio etc) report almost daily on new scientific advancements using stem cells as a treatment (or potential treatment) for many diseases. There is wealth of published literature referencing the ongoing science and research of using UCB and regenerative medicine. Outlined below are just some of the key classes of diseases where UCB stem cells (and other types of stem cells) have been used in therapy as well as some current areas of research. Class of Disease
Example
• Metabolic
Diabetes, glycogen storage disease (GSD), phenylketonuria, liver disease, Tay-Sachs disease, Hunter’s Syndrome
• Oncologic • Immunologic
Various leukaemias, lymphomas, cancers
• Genetic
Sickle cell anaemia, thalassaemia, Fanconi’s anaemia
Multiple sclerosis (MS), Crohn’s disease, lupus, rheumatoid arthritis (RA), chronic granulomatous disease
Extensive research in the area of regenerative medicine is focused on the development of cells, tissues and organs for the purpose of restoring function through transplantation. The general belief is that replacement, repair or restoration of normal function is best accomplished by cells, tissues or organs that can perform the appropriate physiological/metabolic duties better than any mechanical device, recombinant protein or therapeutic or chemical compound. Several strategies are currently being investigated and include cell therapies derived from autologous primary cell isolates, cell therapies derived from established cell lines, stem cells derived from a variety of sources including bone marrow, mesenchymal stem cells, cord blood cells, embryonic stem cells as well as cells, tissues and organs from a variety of genetically modified animals (Fodor, 2003).
Figure 2 – Focus of UCB and Regenerative Medicine
Image Copyright of Japan Tissue Engineering Co. Ltd (J-TEC)
Stem cells - a clinical update
UCB, Cancer and Leukaemia The outcomes of various clinical trials using stem cells in cancer therapy have cited results where fewer infections have been found, accelerated reconstitution of cellular make-up, statistically significant reduction in GvHD and faster haematological recovery (Sagar et al, 2006). The results of two studies published in the New England Journal of Medicine show that UCB is an acceptable alternative of stem cells where a suitable bone marrow donor is unavailable. The findings, reported by European and US research groups offer promising alternative to thousands of leukaemia patients in need of treatment3. At the 6th Annual International Umbilical Cord Blood Transplantation Symposium held in Los Angeles, Assistant Professor Kent Christopherson II PhD, stated that his research as well as others in the same field, had great hope in stem cell therapeutics showing positive results. In a paper presented by Kazumi (2003), the author highlights the use of UCB stem cells to successfully treat a young girl with myelodysplastic syndrome (‘pre-leukaemia’) associated with Behçet disease. Studies conducted by researchers at the University of Minnesota in the US have demonstrated the safety and efficacy of UCB transplantations after non-myeloablative therapy. Moreover, the team’s data support the conclusion that older patients with high-risk haematological diseases can now be offered UCB treatment with nonmyeloablative conditioning as a potential curative treatment option (Brunstein et al, 2007). Other noted publications and research: Patient remains in remission 33 months after cord blood transplant (CBT). CBT thus could be an appropriate source for patients with advanced NK/T lymphoma who have no HLA-matched donors’ (Yokoyama et al, 2007). The use of cancer stem cells has opened new areas of research in carcinogenesis and future treatment options’ (Sagar et al, 2007).
UCB, Cardiac Research and Therapeutics Researchers at Imperial College, London, are perfecting a technique to rebuild a heart severely damaged and scarred by disease or cardiac arrest. This could eventually lead to the end of heart transplants in the UK where heart related conditions kill 238,000 individuals every year1. A study by Schmidt et al (2004) showed that UCB endothelial cells demonstrated excellent growth potential for tissue-engineered vascular grafts that could replace human heart defects. The findings offer a compelling reason why parents with a child diagnosed intrauterinely with congenital defects should consider preserving their childs cord blood since it may offer a treatment option in the future. Research presented at the American Heart Associations (AHA) scientific sessions in 2008 showed that stem cells harvested from UCB can be grown ex-vivo to produce the foundations of new heart valves. Research lead and cardiac surgeon Ralf Sodian M.D said at the conference, ‘tissue engineering provides the prospect of an ideal heart valve substitute that lasts throughout the patients lifetime and has the potential to grow with the recipient and change shape as needed2.’ Clinical trials outlined in a paper by Dimmeler et al (2005) show how transplantation of stem cells (from various sources) in cardiac defects have shown significant improvement in function. The author cites that ‘recent experimental studies early-phase clinical trials lend credence to the visionary goal of enhancing cardiac repair as an achievable therapeutic target.’ In a summary of clinical trials outlined by Renault and Losordo (2008), the authors highlight some of the research into cardiac repair (angiogenesis) using a variety of stem cells. Whilst the authors rightly point out some of the
Stem cells - a clinical update
concerns that go in hand with new therapies, there is clear evidence that the use of stem cells has to date, proved effective and safe. Further research summaries: Heart Repair and Stem Cells (van Laake et al, 2006). Umbilical cord blood derived stem cell therapies designed for regenerative treatments of ischemic diseases of human myocardium (Bonanno et al, 2007). Transplanted human umbilical cord blood mononuclear cells improve left ventricular function through angiogenesis in myocardial infarction (Hu et al, 2006). Cardiac troponin T [in cord blood] may be a useful marker for myocardial damage in neonates’ (Clark et al, 2001). Unchain my heart (paper) – The scientific foundations of cardiac repair’ (Dimmeler et al, 2005).
UCB, Huntington’s, Alzheimer’s and Parkinson’s In 1995 it was suggested that immature stem cells existing in umbilical cord blood (UCB) might have an ameliorating effect on neurological diseases such as Alzheimer’s disease, amyotrophic lateral sclerosis (ALS) and Parkinson’s disease. Since this time, animal models have shown that UCB mononuclear cells significantly delay the onset of these conditions. Furthermore, it has since been shown that this effect was greater than when using BM stem cells (Ende et al, 2002). In pre-clinical studies published in the March 2008 issue of Stem Cells and Development show that stem cells derived from UCB are showing early potential in fighting Alzheimer’s disease5. Cell therapy for Huntington’s disease (paper)’ (Dunnett et al, 2004). In-vivo induced pluripotent stem cell or neural cells through ‘forced gene expression’ can be used to repair damaged brain areas or treat degenerative diseases’ (Yuan et al, 2008). The promise of stem cells in Parkinson’s disease’ (Langston, 2005). The successful generation of an unlimited supply of dopamine neurons will make neurotransmitter transplantation widely available for patients with Parkinson’s disease. ESC are opening an exciting era in human therapeutics’ (Freed, 2002). Cell replacement therapy: helping the brain to repair itself (paper)’ (Lindvall et al, 2004). Widespread effective clinical applications generated by hESC technology will become mainstream over the next decade’ (Ormerod et al, 2006). Activating stem cells may treat Alzheimer’s’ (paper) (Tanne, 2005).
UCB, Stroke and other Neurological Injuries and Conditions Clinical trials have shown that delivery of circulating CD34+ cells from human UCB can produce functional recovery in an animal stroke model with concurrent angiogenesis and neurogenesis leading to some restoration of cortical tissue (Peterson, 2004).
Stem cells - a clinical update
A leading paper published by Ichim et al (2007) highlights the growing success of UCB stem cells in the treatment of autism and associated disorders as well as the stimulation of angiogenesis in various models of ischemia. Research at the University of Illinois College of Medicine headed by Dr Dasari show that human UCB stem cells hold great promise for therapeutic repair after spinal cord injury. The results of this ongoing study show that UCB stem cells are beneficial in reversing the behavioural effects of spinal cord injury (Dasari et al, 2007). Clinical research summarised by Walker et al (2009) showed that various stem cell therapies for traumatic brain injury vastly improved the outcomes of subjects up to 20%. Further research summaries: Umbilical cord blood-derived mesenchymal stem cells were able to transdifferentiate into bone and 2 types of neuronal cells in-vitro (Park et al, 2006). New evidence suggests that delivery of circulating CD34+ human umbilical cord blood cells can produce functional recovery in an animal stroke model (Peterson, 2004). Cell therapy for Huntington’s disease (paper) (Dunnett et al, 2004). In-vivo induced pluripotent stem cell or neural cells through ‘forced gene expression’ can be used to repair damaged brain areas or treat degenerative diseases’ (Yuan et al, 2008). The promise of stem cells in Parkinson’s disease (Langston, 2005). The successful generation of an unlimited supply of dopamine neurons will make neurotransmitter transplantation widely available for patients with Parkinson’s disease. ESC are opening an exciting era in human therapeutics (Freed, 2002). Cell replacement therapy: helping the brain to repair itself (paper) (Lindvall et al, 2004). Widespread effective clinical applications generated by hESC technology will become mainstream over the next decade (Ormerod et al, 2006). Activating stem cells may treat Alzheimer’s’ (paper) (Tanne, 2005). Umbilical cord blood-derived mesenchymal stem cells were able to transdifferentiate into bone and 2 types of neuronal cells in vitro’ (Park et al, 2006). New evidence suggests that delivery of circulating CD34+ human umbilical cord blood cells can produce functional recovery in an animal stroke model’ (Peterson, 2004). hUCB (human umbilical cord blood) facilitate functional recovery after moderate spinal cord injury and may prove to be a useful therapeutic strategy to repair the injured spinal cord’ (Dasari et al, 2007). Results indicate that hUCB-mediated downregulation of Fas and caspases leads to functional recovery of hind limbs of rats after spinal cord injury’ (Dasari et al, 2008).
UCB and Haematological Diseases and Disorders At the first International Symposium on Stem Cell Research and Therapy (2006) scientists from the world over provided an optimistic approach in the use of UCB stem cells in the treatment of haematological malignancies previously thought to be incurable citing UCB-derived stem cells the only viable option in a number of linked disorders.
Stem cells - a clinical update
The successful use of UCB stem cells to treat a wide variety of haematological has been demonstrated. A study by Young et al (2006) highlighted the successful use of UCB to treat severe aplastic anaemia with its low risk of GvHD. Studies by Kim at al (2006) conducted at the College of Medicine, Korea, found that UCB stem cells transplanted into patients with Buerger’s disease and ischemic limb disease had significant improvement in deterioration of limb pain, improved angiogenesis and improved peripheral circulation.
UCB, Bone and Osteogenic Diseases and Conditions Ongoing research by Tomlinson et al (2008) compares the osteogenesis of human embryonic stem cells, UCBderived mesenchymal stem cells and BM-derived stem cells with promising results. The researchers have found that under osteogenic conditions, all three sources of stem cells can differentiate to form osteoblast like cells. Highly successful treatment of malignant infantile osteoporosis (MIOP) using UCB stem cells was outlined by Jaing et al (2006). The recipient used donor UCB that was a 2-loci HLA mismatch. This case suggests that in the event of unmatched donor availability, UCB stem cells are a feasible option for therapy. Other papers of note: Human umbilical cord blood–derived mesenchymal stem cells have been found to have significantly higher osteogenic potential’ (Kim et al, 2008). Successful unrelated cord blood transplantation in a girl with malignant infantile osteoporosis (Jaing et al, 2008).
UCB, Ocular and Diseases and Conditions of the Eyes At the Annual Meeting of the Association for Research in Vision and Ophthalmology held in Florida in 2008, researchers lead by Professor Whei-Yang Kao, announced that stem cells may be used to cure genetic diseases of the eye4.
UCB and Liver Disease Umbilical cord blood cells, fetal liver progenitor cells, adult liver progenitor cells and mature hepatocytes have all been reported to be capable of self-renewal, giving rise to daughter hepatocytes both in vivo and in vitro’ (Bae, 2008). Cell therapy for the diseased liver: from stem cell biology to novel models for hepatotropic human pathogens’ (Brezillion et al, 2008).
UCB and Autoimmune Diseases Stem cell based therapy is a well established approach to treat a wide variety of autoimmune diseases (AD). Dazzi et al (2007) highlights the ongoing research that in the last 10 years has seen significant improvement in the successful use of haemopoietic stem cells for otherwise untreatable forms of AD. Researchers at the University of Illinois, Chicago, have found that by using UCB stem cells in the treatment of type I diabetes there was marked elimination of hyperglycaemia with restored islet function and architecture. The findings of this study outline a new strategy for the prevention and treatment of diabetes and other autoimmune diseases (Zhao et al, 2009). Autologous umbilical cord blood infusion for type I diabetes (Haller et al, 2008).
Stem cells - a clinical update
Human umbilical cord blood mesenchymal stem cells can differentiate into islet-like cells in vitro and extracellular matrix (ECM) gel plays an important role in pancreatic endocrine cell maturation and formation of threedimensional structures’ (Gao et al, 2008). Mesenchymal stem cells: Biology and clinical potential in type I diabetes therapy’ (Liu et al, 2008).
General Overview UCB is a valuable source of stem cells for transplantation in the treatment of a variety of haematological, oncologic, immunologic, and metabolic disorders. In the last few years an increasing number of patients have received cord blood transplants with great success (Tanaka et al, 2006). Various studies have shown, and current therapeutic strategies demand, that stem cells are cryopreserved for virtually all autologous, as well as many allogenic, transplants (Berz et al, 2007). By far, the majority of UCB transplants have occurred in the paediatric setting. This reflects a perspective that the number of stem cells harvested from a typical cord blood collection is limited to infants and young children (Rogers et al, 2001). However, this said, methodologies and techniques to increase the number of viable stem cells and progenitor cells from a single sample are rapidly becoming commonplace. The In-vitro amplification of stem cells will undoubtedly aid in the applicability and success rate of such treatments although optimum collection, processing and storage is of course paramount. Haemopoietic stem cell transplantation is now regarded as a safe and acceptable therapy for many cancers and inherited disorders that originate or manifest as primary abnormalities of the blood or bone marrow (BM). A transplant of this type can use stem cells collected from the patient (autologous) or from a suitably matched donor (allogenic). Donor-recipient compatibility is determined by matching specific Human Leukocyte Antigens (HLA). The degree of homology, i.e. how well the two tissues match, will determine how well the transplant will work. Within families, siblings have a 1 in 4 chance of good HLA homology as each child inherits one of each of the two maternal and paternal haplotypes. Some of the problems encountered with bone marrow (BM) transplants involve finding a suitable match in time for the transplant to happen. Despite there being nearly 10 million registered donors worldwide, only 50% of white patients will find a suitable match (Confer, 1997). In ethnic minorities, this number is much lower, reflecting the lower number of ethnic minorities registering themselves as donors. Clearly, there is a need for stem cells and UCB is prominent in both the research and clinical setting as a therapeutic source of these amazing cells. Figure 3 – In-vitro Differentiation of Stem Cells
Image Copyright of ProQuest, 2008
Stem cells - a clinical update
Diseases and Conditions in Focus Since the advent of stem cell-based therapies to treat a wide variety of diseases and conditions, scientific and medical research has started to focus on the more destructive ailments affecting human health. Below is a list of some of the conditions on which research using UCB stem cells if focused. Type of Disease
Examples
Leukaemias, lymphomas and other bloodcancers
Acute lymphocytic leukaemia (ALL), acute myelogenous leukaemia (AML), Hodgkin’s lymphoma, adult T-cell leukaemia, multiple myeloma
Other cancers
Renal cell carcinoma, neuroblastoma, small-cell lung cancer, brain tumors
Bone marrow disorders
Severe aplastic anaemia, Fanconi anaemia, Blackfan Diamond anaemia, congential cytopenia
Haemoglobulinopathies
Beta thalassaemia major, sickle cell disease
Myeloproliferative disorders
Amyloidosis, acute myelofibrosis, chronic myelomonocytic leukaemia
Inherited metabolic disorders
Hurler’s syndrome, Hunter’s syndrome, Krabbes disease, Lesch-Nyhan syndrome, Tay-Sachs disease, mucolipidosis
Inherited immune disorders
Chronic granulomatous disease, congenital neutropenia, SCID, X-linked lymphoproliferative disorder
As well as the diseases and conditions listed above (which is no way exhaustive) increasing emphasis is being focused on the likes of heart related diseases, brain injury and spinal repair, diabetes and cerebral palsy. Some of the most widely investigated illnesses using stem cells as treatment reflect some of the most common causes of morbidity and mortality of our time. These include a variety of cancers, neurodegenerative disease, autoimmune and metabolic disorders. Figure 4 summarises which types of diseases and conditions are focused on. Figure 4 – Focus of stem cell research as of 2008
Image copyright of New York State Stem Cell Science (NYSTEM). 2008.
Stem cells - a clinical update
As science progresses (as it always does), there is rapidly growing acknowledgement throughout the medical, scientific and academic world that UCB stem cells are a real, acceptable source of therapy for numerous diseases. A leading paper published in the acclaimed Journal of Translational Medicine written by Riordan et al in 2007 summarised the current opinion of the use of UCB stem cells citing the outcomes of treatment for a number of diseases treated using UCB stem cells. Duchenne muscular dystrophy
‘‘…physical examination revealed obvious improvement in walking, turning the body over, and standing up…’
Refractory anaemia
‘…all patients are alive and free of disease at between 17 and 39 months after cord blood administration…’
Spinal cord injury
‘…improved sensory perception and movement…regeneration of the spinal cord at the injured site…’
Non-healing wounds
‘…accelerated healing…’
Malignant infantile osteoporosis
‘…normalisation of spine bone mineral density…’
Rothmund-Thompson Syndrome
‘…complete immune reconstitution…’
Behcet’s disease
‘…Twenty-three months after CBT (cord blood transplant) the patient is doing well and has no signs or symptoms of Behcet’s disease…’
The Law and Stem Cells (United Kingdom) 2008 saw a radical change in the regulation of procurement of cord blood. Given the impact this has made not only to donations to public banks but also to private banks this section is designed to provide a clear understanding of the current legislation and allow healthcare professionals to understand exactly what is needed in order to procure cord blood in accordance with the law. The guidance referred to in this section is taken from the Human Tissue Authority (HTA), the responsible body for enforcement of this legislation in the United Kingdom. …It is imperative to understand that failure to ensure that cord blood procurement is achieved under the auspices of a Human Tissue Authority license (either directly on a licensed premises or by way of a Third Party Agreement) is a breach of the legislation and is therefore an offence under the Human Tissue Act Quality and Safety Regulations 2007.
History Since 2002 private banking of a childs’ umbilical cord blood (UCB) has been possible in the United Kingdom. This option has been widely available in the USA for some preceding 10 years, and is rapidly becoming “the norm”. In the UK, in response to this novel patient demand, the Royal College of Midwives (RCM) published a Position Statement regarding commercial collection of UCB in December 2002. Subsequently, the Royal College of Obstetrics and Gynecology (RCOG) published an Opinion Paper on this matter June 2006. Both these papers noted that patients were increasingly likely to ask for this, and highlighted the important practical issues of liability cover, prioritisation of care and resource availability. Prior to 2002 the options to bank cord blood were limited to USA based companies who shipped the blood back
Stem cells - a clinical update
to the USA for processing and storage. In 2002 the first UK based cord blood bank was opened (Cells4Life Ltd) and was subsequently followed by many more. At present there are four UK based established private cord blood banks, and one recent addition, as well as numerous US and European based operations which have arisen. 2004 saw the introduction of the Human Tissue Act (HT Act), transposed from the European Tissue and Cell Directive 2004 (EUTCD) regulated by the HTA. On 30 April 2008 the HTA announced that the procurement of umbilical cord blood was to be regulated in the same manner as other organ donations, and would therefore require a license. The options for licensing compliance are: 1. A license (present suggested fee for 2009 is £6000) for the institution where cord blood is procured e.g. hospital maternity unit. Clearly this is costly and does not cover home birth scenarios 2. A third party agreement with a licensed institution either with an individual or with another institution who procure cord blood on behalf of the licensed entity
Third Party Agreements Human umbilical cord blood is taken with the express purpose of being used in a therapeutic treatment at some point in the future. This is no different to any other organ or tissue type, with the exception that the use may be many years in the future, and for diseases which are not currently treatable. Procurement must therefore be traceable and occur in a suitable manner and place. Third party agreements (TPA) are specifically provided for in the legislation. It is a formal agreement, legally binding under the HT Act 2004, which specifically makes each party aware of their duties and responsibilities. It includes for instance an obligation to ensure that the person documents any event which may impact the sample. An example would be the mother suffered a haemorrhage which resulted in her receipting a blood transfusion so the maternal blood sample provided would be useless in terms of disease marker testing. It is highly likely that healthcare professionals who work within the NHS are not covered by the NHS insurance if the procurement is taken for any other purpose than NHS use. However there are exceptions where the NHS Trusts have entered into commercial agreements for procurement. It is therefore necessary for each healthcare professional to ensure they are fully aware of the current policy of the hospital they are working for.
What you should do
• •
Ascertain if the organisation you are working for permits cord blood procurement Ascertain if there is either a license OR a third party agreement in place between you, your employer and the company who is supplying the client service
• •
Ensure you are trained in the process of procurement Ensure any documentation is completed, including where relevant details of the birth etc which may affect the sample
Should you be asked to procure blood and you are not sure if there is a TPA in place, please make contact with the organisation in advance. Should blood be procured without a TPA this may adversely affect the storage potential of the sample.
Stem cells - a clinical update
Overcoming Current Limitations The process of procuring and storing UCB for future therapeutic use is a relatively new concept in medicine and because of this there are many problems to overcome in the near future. Various studies which have included doctors, midwives, the public and other various interested parties have shown that many of the problems faced at the moment in cord blood banking stem from the following (Fernandez et al, 2003):
• Lack of public knowledge • Little of no understanding of regenerative medicine • Personal opinions of healthcare professionals (midwives etc) • Lack of utilisation by clinicians • Ongoing debate ‘is there a need for cord blood banking?’ • Cost of private banking • Accessibility of cord blood banking related services • Opponents of cord blood banking making exaggerated, erroneous and misleading statements for their own benefit Overcoming current limitations will take time. Lack of knowledge and misunderstanding exists for a number of reasons. As with all new advances in science and medicine, public perception can be difficult to overcome. Terms such as ‘embryonic stem cell research’ make some people scowl without having any idea what it really is. In early 2008 when the subject of stem cell research was bought up in parliament, MPs were asked to vote on whether is should be allowed or not. In a straw poll conducted after voting it was established that the vast majority of MPs didn’t even have a clue what a stem cell even was. So much misunderstanding comes from individuals who have very little knowledge of what stem cells are and how they tie in with the concept and reality of regenerative medicine. Moreover, it can be difficult to get healthcare professionals to accept new, improved or wholly different standards and/or developments in their specialist fields. Experience has also shown that the personal opinions of some ‘healthcare professionals’ can skew individual decisions. An ongoing example is that of an expectant mother whose first point of call for cord blood banking may well be in conversation with her midwife. If the midwife, and for no legitimate reason disagrees with, or part or whole of the process of cord blood banking, then this generally influences the mothers’ opinion in a negative manner. As with all new concepts in science and medicine, there will always be outright opponents. The fact of the matter is cord blood banking is undertaken entirely of free will and no-one in the industry is forcing the issue. There is a wealth of published scientific literature supporting and proving the benefits of UCB banking and subsequent use. That is a FACT. Most opponents of private cord blood banking have motives that aren’t specifically aimed at cord blood banking, it may be that the concept or business ‘gets in the way’. There is no doubt that we now live in society where the public have such high expectations of scientists and doctors, it is essentially demanded that we find cures and treatments for virtually every illness, disease and condition that affects us. This cannot be done without support and the right approach. Hopefully, with more knowledge, more questions being asked and more interest, the public and healthcare professionals alike will accept that regenerative medicine and the use of UCB as a source of stem cells is here to stay and will soon become commonplace. The problems associated with UCB banking don’t just stem from perception. There are plenty of scientific limitations yet to overcome. Several innovative strategies are aimed at increasing the cell dose are being explored (see below).
Stem cells - a clinical update
Transfusion of a source of stem cells i.e. UCB stem cells, usually occurs via standard blood transfusion techniques. It results in recruitment and differentiation of the transplanted cells as well as recruitment of host cells to the effected area. This has been demonstrated in prominent studies involving retinal surgery, diabetes and cerebral palsy. Strategies to overcome limitations of low cell dose in UCB transplants: CONCEPT
SOLUTION
Using a bridging population during engraftment period
Double unit UCB transplant
Using host cells to bridge engraftment conditioning
Non-myeloablative or reduced sensitivity
Improve homing
Direct injection of UCB cells to target area
Increase the number of stem cells
Ex-vivo expansion of stem cells
Therapeutic cell dose has been hotly debated, with the current figure being approximately 20 millions cells per kg of body weight. Clinical phase I trials using ex-vivo expanded cells are now underway.
Cells4Life – Setting an Example At Cells4Life Ltd we are, and always have been, committed to setting an example in the industry of cord blood banking. At our own established state-of-the-art laboratory based on the University of Sussex, Brighton, we are now the UKs foremost UCB bank. One of the first things that set us aside from other UCB banks in the UK is that as a company, we own and operate our own laboratory with full processing and storage facilities. The majority of other UCB banks use contracted laboratories that do not specialise in UCB processing and storage. Furthermore, by using contracted laboratories, you simply do not get the staff with the specialist knowledge and skills needed to deal with UCB banking. At Cells4Life, all our Medical Scientists, Medical Doctors and Laboratory Technicians are dedicated stem cell specialists. Cells4Life is the only UCB bank in the UK to store whole blood. There is no scientific evidence supporting the use of separated UCB over whole UCB in autologous (or allogenic) transplants. The only benefit of separating whole UCB into its component parts is that of physical space-saving and companies that separate UCB only do so to save money. However, this saving cost is never passed on to the customer. At Cells4Life, we store the whole blood, regardless of volume, at no extra charge. Figure 5 – Cutting of the umbilical cord and procurement of cord blood
Stem cells - a clinical update
At Cells4Life we strive to stay ahead of the game. We have a vast medical library of journals and articles from some of the leading and most well respected institutions in the field which is constantly being updated. Our library of resources includes the Royal College of Obstetrics and Gynecology (RGOG), The Lancet, The New England Journal of Medicine, Transfusion, Bone Marrow Transplant, British Journal of Midwifery, British Medical Journal and Stem Cells to name a few. We are also one of the few companies in our field to have dedicated Medical Doctors and Medical Scientists who specialise in stem cells and transplantation who work only for Cells4Life. Staff training and knowledge is of utmost importance to Cells4Life. Our staff members belong to a variety of government, academic and medical institutions ranging from the Royal College of Surgeons (RCS), The Institute of Biomedical Science (IBMS), The Health Professions Council (HPC) and the Institute of Biology (IB). Table 1 – Storage of Whole UCB (at Cells4Life) vs. Separated UCB Process and/or aspect of storage Processing of specimen Volume of UCB Recovery of stem cells after thawing Viability of UCB Microbial contamination rate
Whole UCB
Separated UCB
Minimal (~30 mins) – dramatically reduces exposure to detrimental elements
Extended (many hours) – increased likelihood of contamination and loss of stem cells Smaller storage space but not reflected in cost No scientific evidence to support increased viability Numerous unnecessary tests that do not relate to transplant viability or potential
Cost is the same, regardless of volume Minimal loss with good recovery of progenitor cells Nucleated cell count, viable cell count (using advanced fluorescent flow cytometry platform FFCP)* Low
Transplant rate
High with good success rate
Side effects of transplantation
Low, mild and reversible
*See Glossary of Terms
High due to increased exposure to detrimental elements, increased manual handling and ambient temperatures No greater than whole UCB transplants No less so than whole UCB
The Future It will take several years of research and clinical trials to determine the exact role ESC and non-ESC will play in regenerative medicine. At present, the mainstay of transfusions are carried out using non-ESC, especially autologous cells, as well being used in clinical trials as well as clinical practice. Commercial cord blood banking at Cells4Life is an established service which offers parents the opportunity to store their baby’s own UCB in the long-term. Should that child or his/her siblings develop any one of a number of metabolic, immunologic or haematologic diseases or conditions then that saved UCB has the potential to save a life. The future of stem cell therapy is secure. With increasing advancements being made in the field of regenerative medicine almost daily, the potential for cures and treatments foe many more conditions and diseases is now within reaching distance. In modern medicine, individuals now have the choice of where they want to be treated, how they want to be treated and most importantly, they have say in it and are listened to. UCB banking is a choice made by parents in the event that there child may become ill and where stem cells are an option for treatment. Stem cell technology, regenerative medicine and future therapies are not miracle cures, they are the result of years of hard work and research by dedicated scientists, doctors and patients that all contribute to the future health of our kind. This group of people will continue to work to ensure that sick individuals have access to the latest medical and scientific advancements.
Stem cells - a clinical update
Glossary Allogenic – being genetically different although belonging to the same species Autologous – derived or transferred from the same individuals body Blastocyst – in mammals, the early result of a fertilised egg Bone Marrow – soft, fatty vascular tissue that fills most bone cavities and a source of red and white blood cells Donor – a person who gives or donates Embryonic Stem Cell (ESC) – cells obtained from the embryo in the blastocyst stage Graft versus Host Disease (GvHD) – a reaction where the cells of a transplanted tissue immunologically attack the cells of the host Haemopoietic Stem Cell (HSC) – a type of stem cell that gives rise to all the other types of blood cells Human Leukocyte Antigen (HLA) – the major class of histocompatibility antigens in humans Human Tissue Authority (HTA) – is the UK non-departmental body created by the Human Tissue Act 2004 which regulates the removal, storage, use and disposal of human bodies and tissues In-vitro – Latin meaning ‘within the glass’. Essentially something carried out in a laboratory In-vivo – Latin meaning ‘within the living’. Essentially something done in a living organism Mitosis – process of cell division in which the nucleus of the cell divides resulting in two daughter cells. Generally consisting of four stages – prophase, metaphase, anaphase and telophase Regenerative Medicine – is essentially medical treatment where stem cells are used to treat and/or cure a variety of conditions and diseases Transplant – to transfer from one body to another (allogenic transplant) or from one part of the body to a different place on the same body (autologous transplant) Umbilical Cord Blood (UCB) – blood collected from the umbilical cord of a term infant. A rich source of stem cells
Stem cells - a clinical update
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Stem cells - a clinical update
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Stem cells - a clinical update
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Stem cells - a clinical update