Research & Innovation

RECENT HIGHLIGHTS

Exciting research at RCSI re ects the contribution scientists make to healthcare and society

GENE DELIVERY

Scientists have developed polypeptide-based materials that act as effective vectors for delivering gene therapies. The platform, which is the first of its kind, enables the vectors to be adapted to suit the specific gene therapy cargo.

The work, led by researchers Professor Sally-Ann Cryan from RCSI University of Medicine and Health Sciences is funded by Science Foundation Ireland (SFI).

“With the success of COVID-19 vaccines, the potential of gene therapies is becoming apparent, and advanced nanoparticle delivery systems are key to enabling their use clinically. We have shown that these nanoparticles have real potential to be a gamechanger in the delivery of gene therapies,” said Professor Sally-Ann Cryan, the study’s senior author and Professor of Drug Delivery, RCSI.

A major challenge for gene therapies is preparing them in a way that can deliver the genetic information into the host cells.

The researchers developed a platform that produces bespoke star-shaped polypeptide nanoparticles, which effectively deliver a range of therapies, including gene therapies. Crucially, these polypeptides are more flexible and easier to handle than lipids. To demonstrate the potential of this material, the researchers used it to deliver a gene therapy that regenerated bone.

In preclinical work, the researchers loaded the material with DNA molecules that promote bones and blood vessels to regrow. They placed these nanomedicines in a scaffold that could be implanted into a defect site and deliver the genetic cargo into infiltrating host cells. The geneloaded scaffold accelerated bone tissue regeneration, with a six-fold increase in new bone formation compared to a scaffold alone.

“While more testing is needed before these therapies can be used clinically, our platform allows us to design our polypeptides to meet a variety of delivery scenarios and provide tailored solutions to gene delivery challenges,” said Professor Andreas Heise, project collaborator and Professor of Polymer Chemistry, RCSI. “We are developing this patent-protected technology towards commercialisation, with support from an Enterprise Ireland Commercialisation Fund Award, and are seeking expressions of interest from industry partners and investors.”

BLOOD CLOTTING AND LONG COVID

A new study of 50 patients, led by researchers from RCSI and published in the Journal of Thrombosis and Haemostasis, shows that patients with Long COVID syndrome continue to have higher measures of blood clotting, which may help explain persistent symptoms, such as reduced physical fitness and fatigue. Previous work by the same group studied the dangerous clotting observed in patients with severe acute COVID-19. They discovered that clotting markers were significantly elevated in the blood of patients with Long COVID syndrome compared with healthy controls.

“Our results suggest that the clotting system may be involved in the root cause of Long COVID syndrome,” said Dr Helen Fogarty, the study’s lead author, ICAT Fellow and PhD student at the Irish Centre for Vascular Biology in the RCSI School of Pharmacy and Biomolecular Sciences. “Millions of people are already dealing with the symptoms of Long COVID syndrome. It is imperative that we continue to study this condition and develop effective treatments,” said Professor James O’Donnell, Director of the Irish Centre for Vascular Biology, RCSI and Consultant Haematologist in the National Coagulation Centre in St James’s Hospital, Dublin.

The study was funded by the Wellcome Trust, the Health Research Board, the Irish Clinical Academic Training programme and the Irish COVID-19 Vasculopathy Study and was supported by a philanthropic grant from the 3M Foundation.

Professor Hannah McGee and Professor Fergal O’Brien with Lorna Kerin, RCSI PPI Manager, and RCSI colleagues.

A NATIONAL NETWORK

RCSI marked its participation in the national public and patient involvement “Ignite” Network in November 2021, as part of the official launch of the network, co-funded by the Health Research Board and the Irish Research Council.

The PPI Ignite Network is a collaboration between seven Irish universities and over 60 partner organisations, including patient organisations at both national and local levels.

Public and patient involvement (PPI) in research involves people with lived experience of a healthcare condition or health service working in partnership with research teams to determine research priorities and how best to carry out that research.

RCSI, one of seven lead PPI Ignite Network sites, coordinated by NUIG and including TCD, UCC, DCU, UCD and UL, will build its internal PPI capacity and develop innovative new PPI programmes both locally and across the network. Local RCSI partners include Future Neuro, the SFI Research Centre for Chronic and Rare Neurological Diseases hosted by RCSI, HSE Digital Transformation, Alpha-1 Foundation Ireland, RCSI Clinical Research Centre and the Irish Heart Foundation.

“The Ignite Network represents a fantastic opportunity to share resources across institutes, in a manner that speeds effective and impactful integration of the public and patient voice to health research,” said Professor Gianpiero Cavalleri, RCSI PPI Ignite Network Site Lead. Lorna Kerin, RCSI PPI Manager, described it as “a privilege to support the strategic and operational development of policies, procedures and practises that will embed public and patient involvement throughout RCSI.”

PSYCHOTIC DISORDERS

An RCSI-led PhD consortium is one of three expert teams awarded funding as part of an investment by the Health Research Board under the Collaborative Doctoral Awards 2021. The award will provide structured training for up to five PhD candidates and will fund a research programme on health and care in psychotic disorders.

The RCSI consortium, PSychosis Ireland Structured Training and Research Programme (PSI-STAR) is led by Professor David Cotter with co-leads Professor Mary Cannon, RCSI, and Professor Agnes Higgins, TCD and with PPI lead, Dr Mike Watts of GROW, a community-based mental health support organisation.

PSI-STAR is a collaboration with clinicians and researchers from Maynooth University, Queen’s University, NUIG, UCD and UCC. Collaborators include HSE and Mental Health Commission partners but, most critically, a deep representation from Irish Patient and Family Advocacy groups including SHINE, Mental Health Reform, Mental Health Engagement and Recovery, Irish Advocacy Network as well as Spunout. The PSI-STAR will develop an all-Ireland integrated network of clinicians and researchers from the disciplines of psychiatry, nursing, social work, sociology and psychology, as well as policymakers, who will foster, support and implement findings of clinically-oriented research into psychosis care in Ireland.

“Psychotic disorders such as schizophrenia and bipolar disorder occur in about three in 100 people. They usually start in adolescence or young adulthood and can have a devastating impact on a young person’s education, family and social relationships and career,” said Professor David Cotter, Professor of Molecular Psychiatry at RCSI, Consultant Psychiatrist at Beaumont Hospital, Dublin and investigator at FutureNeuro, the SFI research centre for chronic and rare neurological diseases. “It is critical that people are diagnosed in the early stages of psychosis, or even just before it begins, so that the best treatments and supports can be offered as soon as possible. I am looking forward to the training and research outcomes from the PSI-STAR programme that have the potential to drive early interventions that will potentially aid the recovery of people with psychosis.”

BACTERIA & BOWEL CANCER

New research has found a possible relationship between a specific type of bacteria found in tumours and the spread of bowel cancer. Published in the leading gastroenterology journal, Gut, the research can help clinicians identify patients at risk and make decisions on treatment options for patients with bowel cancer whose tumours are infected with the bacterium Fusobacterium nucleatum. This collection of bacteria, which normally lives in the oral cavity, infects bowel tumours, changes how tumour cells behave, and may

trigger the spread of the tumour to other organs. Using genomic sequencing, researchers are now able to detect traces of an infection with bacteria or other microbes in patients’ tumours that previously would have been undetectable. The RCSI-led research set out to understand which tumours are infected with bacteria, and what the role of a bacterial infection means in terms of how the disease progresses. Professor Jochen Prehn Lead researcher, Jochen Prehn, Professor of Physiology and Director of the Centre for Systems Medicine at RCSI, said: “An effective tool to help oncologists to personalise colorectal cancer treatment is urgently needed. We hope these findings will enhance diagnostics to improve the efficacy of current treatment and help further advance the use of new therapeutics for patients infected with this bacterium.”

A NOVEL WAY TO REPAIR NERVE DAMAGE

Researchers from RCSI and AMBER, the SFI Research Centre for Advanced Materials and BioEngineering Research, along with leading global medical technology company Integra LifeSciences, have discovered a new breakthrough for nerve repair therapies based on the body’s own processes. The research was published in the journal Matrix Biology with Drs Alan Hibbitts and Zuzana Kočí the lead authors of the study.

The preclinical study showed that use of extracellular matrix (ECM) supports improved nerve fibre regeneration across large nerve defects without the need for application of additional cells or growth factors. In these preclinical trials, the team’s novel ECM-loaded medical device known as a ‘nerve guidance conduit’, was shown to support improved recovery responses at eight weeks following the repair of traumatic nerve lacerations with substantial loss of tissue.

The research team found that by finetuning the combination and ratio of ECM proteins and loading them into the nerve guidance conduit, it was possible to support increased pro-repair inflammation, increased blood vessel density, and increased density of regenerating nerves, all as compared to standard of care. By mimicking the body’s nerve repair processes, this new approach may eliminate the need for additional stem cells and drug therapies.

Peripheral nerve injury is a major clinical problem and is known to affect more than five million people worldwide every year, leaving those afflicted with loss of motor or sensory function to muscles or skin. Current therapies to repair nerve damage involve transplanting the patients’ healthy nerves to repair damage or implanting an artificial nerve guidance conduit. The team’s novel patented approach to nerve repair has been shown to increase the density of regenerating long-nerve structures, known as axons, and to generate a strong increase in blood vessel density to better support the regenerating tissues.

Dr Annie Curtis

A DISRUPTED BODY CLOCK AND INFLAMMATORY DISEASE

New research from RCSI has demonstrated the significant role that an irregular body clock plays in driving inflammation in the body’s immune cells, with implications for the most serious and prevalent diseases in humans. Published in Frontiers of Immunology, the research was led by the School of Pharmacy and Biomolecular Sciences at RCSI.

The circadian body clock generates 24-hour rhythms that keep humans healthy and in time with the day/night cycle. This includes regulating the rhythm of the body’s own (innate) immune cells called macrophages. When these cell rhythms are disrupted due to things like erratic eating/sleeping patterns or shift work, the cells produce molecules that drive inflammation. This can lead to chronic inflammatory diseases such as heart disease, obesity, arthritis, diabetes and cancer, and also impact our ability to fight infection.

In this study, researchers found that macrophages without a body clock took up far more glucose and broke it down more quickly than normal cells. They also found that, in the mitochondria (the cells’ energy powerhouse), the pathways by which glucose was further broken down to produce energy were very different in macrophages without a clock. This led to the production of reactive oxygen species (ROS), which further fuelled inflammation.

Dr George Timmons, lead author on the study, said: “Our results add to the growing body of work showing why disruption of our body clock leads to inflammatory and infectious disease, and one of the aspects is fuel usage at the level of key immune cells such as macrophages.”

Dr Annie Curtis, Senior Lecturer at RCSI School of Pharmacy and Biomolecular Sciences and senior author on the paper, added: “This study also shows that anything which negatively impacts on our body clocks, such as insufficient sleep and not enough daylight, can impact on the ability of our immune system to work effectively.”

RCSI conducted the study in collaboration with researchers from Swansea University, TCD and University of Bristol.

3D PRINTING OF BLOOD PLASMA

New research by RCSI suggests that effective wound healing may be aided by replicating a crucial component of our blood. The finding, published in Advanced Functional Materials, was discovered by researchers at the Tissue Engineering Research Group (TERG) and SFI AMBER Centre based at RCSI’s Department of Anatomy and Regenerative Medicine.

This study explores ways of enhancing the wound-healing process by extracting platelet-rich plasma (PRP) from the blood of a patient with a complex skin wound and manipulating it through 3D printing to form an implant for tissue repair to treat difficult-to-heal skin wounds in a single surgical procedure. Results showed that application of the 3D-printed PRP implant helped to speed up the healing of the wound by enabling efficient development of new blood vessels and inhibiting scarring and thickening of tissue, both essential for effective wound healing. Professor Fergal O’Brien, Professor of Bioengineering and Regenerative Medicine at RCSI, explained: “As well as promising results for skin wound healing, this technology can potentially be used to regenerate different tissues, therefore dramatically influencing the ever-growing regenerative medicine, 3D printing and personalised medicine markets.”

Funding for this project came from Science Foundation Ireland (SFI) under the M-ERA.NET EU Network and the Advanced Materials and BioEngineering Research Centre, and the EU BlueHuman Interreg Atlantic Area Project.

The RCSI research team collaborated with researchers from the #Bs Research Group at University of Minho and JCVS/3Bs Associate Laboratory in Portugal, the Trinity Centre for Biomedical Engineering and AMBER, the SFI Centre for Advanced Materials and Bioengineering Research.

Dr Damir Varešlija and Professor Leonie Young

SECONDARY BREAST CANCER

A study led by researchers at RCSI and the Beaumont RCSI Cancer Centre (BRCC) has revealed a potential new way to treat secondary breast cancer that has spread to the brain, using existing drugs. The study, published in Nature Communications, was funded by Breast Cancer Ireland with support from Breast Cancer Now and SFI.

The RCSI study focused on genetically tracking the tumour evolution from diagnosis of primary breast to the metastatic spread in the brain in cancer patients. The researchers found that almost half of the tumours had changes in the way they repair their DNA, making these tumours vulnerable to an existing type of drug known as a PARP inhibitor. PARP inhibitor drugs work by preventing cancer cells to repair their DNA, which results in the cancer cells dying.

“Our study represents an important development in getting one step closer to a potential treatment for patients with this devastating complication of breast cancer,” commented Professor Leonie Young, the study’s Principal Investigator. “By uncovering these new vulnerabilities in DNA pathways in brain metastasis, our research opens up the possibility of novel treatment strategies for patients who previously had limited targeted therapy options,” said study author Dr Damir Varešlija.

The research, led by Beaumont RCSI Cancer Centre investigators Professor Leonie Young, Dr Nicola Cosgrove, Dr Damir Varešlija and Professor Arnold Hill, was carried out in collaboration with the Mayo Clinic and University of Pittsburgh, USA.

RED MEAT AND DISEASE

A team of experts led by Professor Alice Stanton, RCSI School of Pharmacy and Biomolecular Sciences, has called on the Global Burden of Diseases, Injuries and Risk Factors Study (GBD) to make public the evidence which led to the conclusions of its most recent report that links red meat consumption to certain diseases.

In a letter published in The Lancet, the academics raise concerns about the substantial differences in estimates of disease burdens attributable to dietary risk factors, included in GBD 2019 study by comparison with the previously published GBD 2017 study.

The letter states: “the 2019 estimates of deaths attributable to unprocessed red meat intake have increased 36-fold, and estimates of DALYs attributable to unprocessed red meat intake have increased 18-fold.” DALYs are an internationally recognised measure of the impact of diseases on populations.

Based on these findings the GBD 2019 reported that red meat intake contributes to the causation of a range of diseases, including heart disease, breast cancer and stroke, in addition to diabetes and colon cancer. It appears that the dramatic increase in the 2019 estimates is dependent on two assumptions; that the optimal intake of red meat is zero; and that risk rises sharply even with moderate consumption of red meat.

Professor Alice Stanton said: “It is of considerable concern that the GBD 2019 study provides little or no evidence regarding the scientific basis for the assumption that even a moderate consumption of red meat results in a sharp increases in risk of cancers, heart attacks and strokes.”

The letter recommends that the GBD 2019 dietary risk estimates are not used in any national or international policy documents until comprehensive independent peer reviews have been conducted of the evidence underpinning the revised estimates.

Industry Engagement

In 2015, Professor Sally-Ann Cryan, Professor of Drug Delivery in the School of Pharmacy and Biomolecular Sciences, entered a six-year collaborative research programme with Aerogen, co-funded by SFI Research Centre for Medical Devices, CÚRAM. The RCSI-Aerogen research project was entered into the Knowledge Transfer Ireland Awards in 2021 in the Industry Engagement Impact Award category, which recognises and celebrates knowledge transfer success when Irish publicly funded research performing organisations and companies work together.

Outputs from the programme have enabled Aerogen to deepen its engagement with potential pharma and biotech customers by demonstrating their detailed knowledge of emerging therapeutic strategies and novel drug delivery materials.

Research engagement between RCSI and Aerogen now spans the spectrum of preclinical and clinical research and has recently developed into undergraduate and postgraduate education. In October 2020, the Higher Education Authority awarded €7.8m to the School of Pharmacy and Biomolecular Sciences to expand their focus on emerging and future pharma technologies. “Enabling Future Pharma – Beyond the Pill” will develop a suite of innovative programmes in partnership with industry. Aerogen is one of the founding industry partners in the programme, delivering lectures, hosting students and participating in the programme steering board.

A NEW TREATMENT OPTION FOR COVID-19

A clinical trial conducted by researchers from RCSI and Beaumont Hospital and St James’s Hospital Dublin has indicated an effective treatment for critically ill COVID-19 patients.

The study, published in Med, investigates the effects of using antiinflammatory protein, alpha-1 antitryspin (AAT), to treat COVID-19 patients, who have progressed to acute respiratory distress syndrome (ARDS). ARDS is a highly inflammatory state hallmarked by airway damage, respiratory failure and increased risk of death. Treatment options for COVID-19 patients who have ARDS are particularly limited.

AAT is a naturally occurring human protein produced by the liver and released into the bloodstream which normally acts to protect the lungs from the destructive actions of common illnesses. In this randomised controlled trial, AAT that had been purified from the blood of healthy donors was administered to patients with COVID-19-associated ARDS, with the aim of reducing inflammation.

The results indicated that treatment with AAT led to decreased inflammation after one week. The study also found that the treatment was safe and well tolerated, and did not interfere with patients’ ability to generate their own protective response to COVID-19. This discovery suggests a potentially important role for AAT in the treatment of ARDS and other inflammatory diseases associated with COVID-19.

A NEW TREATMENT FOR SEPSIS

Newly created RCSI spin-out company Inthelia Therapeutics is developing a potential new treatment for sepsis, also known as blood poisoning, which kills more people in Ireland than heart attack, lung, colon and breast cancer combined. A staggering 60% of all hospital deaths in Ireland are related to sepsis. Worldwide, there are an estimated 50 million new cases of sepsis each year, with 11 million deaths.

Sepsis is caused by bacteria from a primary infection gaining entry to the bloodstream. For example, urinary tract infections, pneumonia, appendicitis or even a simple cut, scrape or break in the skin can lead to sepsis and rapidly cause multiple organ failure, if untreated. In many cases, antibiotics are not effective due to drug resistance or delays in identifying the type of bacteria that has caused the infection.

Research by Professor Steve Kerrigan, RCSI School of Pharmacy and Biomolecular Sciences and Founder/Chief Scientific Officer of Inthelia Therapeutics, has revealed that non-antibiotic drug Cilengitide has the potential to stop all sepsis-causing pathogens from taking hold in the early stages of the condition and can also potentially stop sepsis from causing organ failure in the later stages of the condition.

Inthelia is now seeking investment to fund the completion of a human clinical trial in sepsis patients. Further research is also taking place on the impact of Cilengitide on COVID-19 after initial results indicated that it could play an important role in preventing the virus from attaching to the cells in the lungs and blood vessels, key events leading to respiratory distress and Long COVID.

Professor Steve Kerrigan was awarded the Vice Chancellor’s Commercialisation Innovation Award at RCSI Research Day 2022 for commercialisation of his research through Inthelia Therapeutics.

Professor Steve Kerrigan

HIGH CHOLESTEROL AND HEART DISEASE

New research has revealed that the link between “bad” cholesterol (LDL-C) and poor health outcomes, such as heart attack and stroke, may not be as strong as previously thought. Published in JAMA Internal Medicine, the research questions the efficacy of statins when prescribed with the aim of lowering LDL-C and therefore reducing the risk of cardiovascular disease (CVD).

Previous research has suggested that using statins to lower LDL-C positively affects health outcomes, and this is reflected in various iterations of expert guidelines for the prevention of CVD. Statins are now commonly prescribed by doctors, with one third of Irish adults over the age of 50 taking statins, according to previous research.

The research demonstrates that lowering LDL-C using statins had an inconsistent and inconclusive impact on CVD outcomes such as myocardial infarction, stroke, and all-cause mortality. In addition, it indicates that the overall benefit of taking statins may be small and will vary depending on an individual’s personal risk factors.

Lead author on the paper Dr Paula Byrne from the HRB Centre for Primary Care Research in RCSI’s Department of General Practice, commented: “Our research indicates that the benefits of taking statins are varied and can be quite modest.” The researchers go on to suggest that this updated information should be communicated to patients through informed clinical decision-making and updated clinical guidelines and policy.

This important discovery was a collaboration with Professor Susan M Smith, also of RCSI and with researchers from the University of New Mexico, USA, the Institute for Scientific Freedom in Denmark, Bond University in Australia and independent researcher Dr Kirsty O’Brien. ■