13 minute read
Research Studies For Better Health
from 2024 RCSI Alumni Magazine
by RCSI
From treatments for multiple myeloma, sepsis and bone infections, to lung conditions and spine fractures, 10 RCSI research projects are helping lead the world to better health
1. Treatment for multiple myeloma
RCSI research, published in Haematologica, has found that venetoclax, a medication currently approved for leukaemia, has benefits for patients with multiple myeloma when used in combination with another drug. This discovery offers a new avenue of treatment options for the currently incurable disease.
Multiple myeloma (MM) is a type of blood cancer that is newly diagnosed in around 400 people in Ireland each year. The search for innovative treatment strategies is crucial, particularly for patients whose cancer is resistant to standard care.
Although previously tested in MM, venetoclax, which blocks the function of a protein called BCL-2, was only found to be effective for a small proportion of patients. The researchers discovered that combining venetoclax with a drug called 5-azacytidine significantly increased its effectiveness, indicating a broader potential patient population that could be treated with the new combination.
“This shows the benefits of re-evaluating existing treatments in new contexts to expand their potential,” said Professor Tríona Ní Chonghaile, Associate Professor, Department of Physiology and Medical Physics and research lead, alongside Lyndsey Flanagan, first author. Professor Siobhán Glavey, Chair, RCSI Department of Pathology and Clinician Scientist, Beaumont RCSI Cancer Centre says they will now test for efficacy and safety in a clinical trial setting to get closer to offering a new treatment strategy for patients.
2. The impact of lockdowns on newborns
Lockdowns imposed during the COVID-19 pandemic had an impact on the gut microbiome development of babies born during these periods, according to new research from RCSI and collaborators.
Professor Jonathan Hourihane, Head of the Department of Paediatrics at RCSI and Consultant Paediatrician at Children’s Health Ireland Temple Street, who is joint senior author, commented on the implications of the research: “This study offers a new perspective on the impact of social isolation in early life on the gut microbiome. Notably, the lower allergy rates among newborns during the lockdown could highlight the impact of lifestyle and environmental factors, such as frequent antibiotic use, on the rise of allergic diseases. We hope to re-examine these children when they are five years old to see if there are longer-term impacts of these interesting changes in early gut microbiome.”
Professor Liam O’Mahony, Principal Investigator at APC Microbiome Ireland and Professor of Immunology at UCC, is joint senior author of the study, published in Allergy: “While we all start life sterile, communities of beneficial microbes that inhabit our gut develop over the first years of life. We took the opportunity to study microbiome development in infants raised during the early COVID-19 era when strict social distancing restrictions were in place, as the complexity of early life exposures was reduced and this facilitated a more accurate identification of the key early-life exposures. Prior to this study it has been difficult to fully determine the relative contribution of these multiple environmental exposures and dietary factors on early-life microbiome development.”
3. Weight loss & diabetes
Researchers in the School of Population Health at RCSI have provided new evidence of the health benefits of weight-loss efforts that lead to diabetes remission for type 2 diabetes patients.
While previous trials have shown that substantial weight loss using diet and lifestyle can reverse type 2 diabetes, the new research shows that reversal of diabetes in turn affects cardiovascular and kidney disease outcomes.
Published in Diabetologia, the study, called Look AHEAD (Action for Health in Diabetes), monitored over 5,000 patients during a period of 12 years. The magnitude of risk reduction was greatest for participants with evidence of at least four years of remission.
For participants in the weight-loss trial who were able to achieve remission, i.e. reduce the need for medications and reduce their HbA1c levels (a measure of blood sugar control), the research found there was a 40% lower rate of cardiovascular disease and 33% lower rate of chronic kidney disease in this group.
Professor Edward Gregg, Head of the RCSI School of Population Health, pointed out that lessons learned from this study can help inform diabetes treatment methods and improve quality of life for people with type 2 diabetes. “It has highlighted the significance of weight loss for achieving remission from type 2 diabetes and long-term positive cardiovascular and kidney disease outcomes,” said Professor Gregg.
4. Reducing bacterial infection and speeding up bone healing
Researchers at the RCSI Tissue Engineering Research Group (TERG) and SFI Advanced Materials and Bioengineering Research Centre (AMBER) have developed a new surgical implant that has the potential to transform the treatment of complex bone infections, detailed in a paper in the journal Advanced Materials When a bone is infected, the priority is to treat it quickly. Standard clinical treatment, including several weeks with antibiotics and often removal of the infected portion of bone tissue, can be slow. Around half of bone infections are caused by MRSA, which is resistant to antibiotics, and prolonged antibiotic treatment pushes up the risk of infections becoming tolerant to the treatments we have at our disposal, making infections harder to control.
To help treat such patients, researchers at RCSI created a material from a substance that is similar to our bones. The scaffold-like structure of this material means that when it is implanted onto injured or diseased bone, it encourages the bone to regrow.
RCSI researchers infused the scaffold with tiny nanoparticles of copper, which are known to kill the bacterium that causes most bone infections. They also incorporated a specific genetic molecule, an inhibitor of microRNA-138, into the scaffold to stimulate the formation of new bone at the site where the material is implanted. Preclinical lab tests showed the implanted scaffolds with the copper nanoparticles and microRNA could stimulate bone regrowth in a fortnight, and that the scaffold stopped 80% of potentially harmful bacteria from attaching to the site. They also saw that the implants stimulated a good blood supply to cells on the scaffold, which is crucial for the health and viability of the newly formed bone.
“We combined the power of antimicrobial implants and gene therapies, leading to a holistic system which repairs bone and prevents infection,” says first author of the study Dr Joanna Sadowska, a Marie Skłodowska-Curie Postdoctoral Fellow at the RCSI TERG.
Professor of Bioengineering and Regenerative Medicine at RCSI, Professor Fergal O’Brien, principal investigator on the paper and Head of TERG, sees many potential benefits to the implant. “The nature of the implant also means that the body can naturally break down the material when the bone heals, so there is no need to remove it surgically.”
The novel nature of this research was recognised last year during the annual meeting of the Orthopaedic Research Society in Dallas, Texas, where Dr Sadowska was awarded a New Investigator Recognition Award for outstanding scientific paper. This is one of the most prestigious global international orthopaedic awards for early-career researchers in the musculoskeletal field.
5. Regenerative treatment for osteoporotic fractures
Dr Ciara Murphy, Lecturer at RCSI Department of Anatomy and Regenerative Medicine and RCSI Tissue Engineering Research Group has received a €2m Consolidator Grant from the European Research Council (ERC) to develop a regenerative stenting technology that will revolutionise the treatment of vertebral fractures in osteoporotic patients. Dr Murphy said: “I am thrilled and privileged to receive an ERC Consolidator Grant to develop a technology that will provide a safe and reparative treatment strategy for patients suffering from osteoporotic vertebral fractures, a common and debilitating condition. I envision a future whereby it is possible to restore the structural and mechanical health to the spine, allowing patients to live a normal and healthy life.”
Vertebral fractures in the spine are the most common complication of osteoporosis, occurring due to damaged and weakened bone structure. Current treatment involves injecting bone cement into fractured vertebrae to support the spine, but this often leads to further fractures and high mortality rates.
Fusing cutting-edge manufacturing techniques and 3D printing with nanotherapeutics, this project will develop a minimally-invasive dual component platform – a biodegradable stent to support fractured vertebrae during healing, and an injectable nano-therapeutic biomaterial targeting damaged bone to drive regeneration and repair.
The new project – RESTORE (REgenerative STenting for Osteoporotic vertebral fracture REpair) will run for five years, starting in June 2024.
6. A new treatment for sepsis
Professor Steve Kerrigan from the School of Pharmacy and Biomolecular Sciences at RCSI has been named winner of the Science Foundation Ireland (SFI) Commercialisation Award 2023. The SFI Commercialisation Award recognises an entrepreneurial or innovation leadership achievement that has resulted in a significant and demonstrable commercial impact and celebrates the entrepreneurial motivation, attitude, and skill required in translating publicly funded research to market.
The award recognises Professor Kerrigan’s contribution as a founder of Inthelia Therapeutics, an RCSI spin-out clinical-stage pharmaceutical company that aims to develop personalised therapeutic approaches to treat patients with sepsis.
Sepsis is the leading cause of death worldwide, causing over 11 million deaths globally per year, and there is currently no drug available to treat the condition. “Through Inthelia Therapeutics, I am proud to lead the advancement of an innovative biomarkerguided, host-targeted therapy towards late-stage clinical trials in early sepsis. I hope the work of Inthelia will ultimately make a significant impact on the treatment and outcomes for sepsis,” said Professor Kerrigan.
7. Therapy for lung condition AATD
Boosting levels of a deficient protein has clear survival benefits for people with the genetic condition alpha-1 antitrypsin deficiency (AATD), according to new research led by RCSI, and published in the American Journal of Respiratory and Critical Care Medicine.
People with severe AATD are born with very low levels of a protective protein called alpha-1 antitrypsin, and they can develop serious lung and liver disease.
“We showed that by boosting this protein in people who are born with very little of it, it is possible to protect them against early death caused by lung disease,” said the study’s first author Dr Daniel Fraughen, from the Irish Centre for Genetic Lung Disease, based at RCSI’s Department of Medicine, who worked alongside study co-author Dr Tomás Carroll, a Senior Lecturer at RCSI and Chief Scientist at the patient advocate organisation Alpha-1 Foundation Ireland.
The findings also point to the need for early detection of AATD and to include younger and healthier patients in studies of augmentation therapy, a form of medication not generally available in Ireland, unlike other European countries, notes study senior co-author Professor Gerry McElvaney, RCSI Professor of Medicine. “Future studies of augmentation therapy should recruit younger patients with less severe lung disease,” says Professor McElvaney. “Detecting people with severe AATD as early as possible and intervening before the establishment of lung disease should be the goal to improve survival. This may require newborn screening for AATD.”
8. Understanding cystic fibrosis in young children
A major new study led by RCSI and Children’s Health Ireland (CHI) has been awarded funding of €5.6m to work with babies and children in Ireland and the UK over the next five years to build a better understanding of cystic fibrosis (CF). Ireland has the highest incidence of CF, an inherited disease that mainly affects the lungs and digestive system, in the world: approximately 1,400 children and adults in Ireland live with the condition and typically more than 30 new cases of CF are diagnosed here each year, usually in the first few weeks of life.
Children born in the 2020s with cystic fibrosis often have more treatment options and potentially better outcomes than those born with the disease in previous decades but there is still much to understand about cystic fibrosis in babies and children in this new era of care.
The ENHANCE study – Establishing Natural History in an Advanced New CF Care Era – will be carried out at 13 paediatric CF clinic sites in Ireland and the UK. RCSI’s Professor Paul McNally, Associate Professor of Paediatrics at RCSI and Consultant in Respiratory Medicine at Children’s Health Ireland, will lead ENHANCE with Jane Davies, a consultant in paediatric respiratory medicine at Royal Brompton Hospital, part of Guy’s & St Thomas’ NHS Foundation Trust.
“We want to ensure we are concentrating on the things that are most relevant to children with CF and their parents in this new era. Parents of children with CF will help us to ensure that we stay focused on our goals.”
9. New insights on epilepsy
The largest genetic study of its kind, coordinated by the International League Against Epilepsy, including scientists from FutureNeuro at RCSI, has discovered specific changes in DNA that increase the risk of developing epilepsy. Epilepsy, a common brain disorder of which there are many different types, is known to have genetic components and sometimes runs in families. In this new study, researchers compared the DNA from diverse groups of almost 30,000 people with epilepsy to the DNA of 52,500 people without epilepsy. Researchers identified 26 distinct areas in DNA that appear to be linked to epilepsy, including 19 that are specific to a particular form of epilepsy called Genetic Generalised Epilepsy (GGE). They were also able to point to 29 genes that are probably contributing to epilepsy within these DNA regions.
“Gaining a better understanding of the genetic underpinnings of epilepsy is key to developing new therapeutic options, and consequently a better quality of life for the over 50 million people globally living with epilepsy,” said Professor Gianpiero Cavalleri, Professor of Human Genetics at RCSI School of Pharmacy and Biomolecular Science and Deputy Director SFI FutureNeuro Research Centre.
10. Hazardous health risks from flavoured vapes
New RCSI research has uncovered the potentially harmful substances that are produced when e-liquids in vaping devices are heated for inhalation. The research team in RCSI’s Department of Chemistry used artificial intelligence (AI) to simulate the effects of heating e-liquid flavour chemicals found in nicotine vapes. They included all 180 known e-liquid flavour chemicals, predicting the new compounds formed when these substances are heated within a vaping device immediately prior to inhalation. The analysis revealed the formation of many hazardous chemicals including 127 that are classified as ‘acute toxic’, 153 as ‘health hazards’ and 225 as ‘irritants’. These included a group of chemicals called volatile carbonyls (VCs), which are known to pose health risks. Sources for VCs were predicted to be the most popular fruit, candy and dessert-flavoured products. Lead author Professor Donal O’Shea, Professor of Chemistry, said the findings are very concerning: “We wanted to understand, before it’s too late, the likely impact flavoured vapes are having on the health of the growing number of vapers. It is plausible that we are on the cusp of a new wave of chronic diseases that will emerge 15 to 20 years from now due to these exposures.” ■
