The MRC Toxicology Unit and Department of Biochemistry at the University of Cambridge, AstraZeneca, Cancer Research UK Scotland Institute, and the Mary Lyon Centre at MRC Harwell have been awarded a £3.4 million MRC Prosperity Partnership grant to fund research into understanding the safety profile of advanced therapeutics. Prosperity Partnerships are awarded by UKRI-MRC to support emerging or established research partnerships between businesses and academic partners.
Nucleic acid therapies (NATs) are advanced therapeutics that target specific DNA and RNA molecules in the cell, enabling treatment of previously undruggable disease targets. Whilst NATs can be used to treat many types of diseases, they can be especially useful for rare diseases. These include diseases such as Duchenne muscular dystrophy, spinal muscular atrophy, and transthyretin amyloidosis, which require a specialised approach to treat a small number of patients. The designable nature of NATs means that a new nucleic acid treatment could be made for each disease-causing DNA or RNA molecule.
Increased understanding of the processes involved in disease development and improvements of NAT platforms, have resulted in a rapid increase of NAT studies and drug approvals. However, adverse events have resulted in the failure of some clinical trials. A deeper understanding of how NATs work at the molecular level in organs like the liver, kidney and immune system will enable a more efficient drug discovery process with reduced risks for adverse events in treated individuals.
Using the expertise of multiple institutes and research groups, the Prosperity Partnership will investigate the common pathways by which NATs trigger toxicities. As part of this research the combined team will generate new laboratory models to mimic human cells and tissues, enabling the study of human specific biological pathways involved in responses to these types of treatment. The partnership will also combine existing and newly generated toxicology data with artificial intelligence and machine learning (AI/ML) models to predict which NATs are most likely to present a safety risk.
Professor Anne Willis, Director of the MRC Toxicology Unit and academic lead on the partnership, explains the importance of this initiative “A deeper understanding of how NATs interact with our cells and tissues will help us predict if side effects will occur. Our aim is to make NATs safer-by-design, using new tools and methods to reduce safety concerns and thus unlock NATs potential to transform healthcare. This work will complement our recently funded INTREPID (IN vitro TumouR Explant models for evaluating cancer complexity and Patient Diversity) Programme to develop human tumour explant models and support alternatives to in vivo testing”.
Achieving this important task requires complementary expertise from all five organisations, including in RNA biology, toxic mechanisms, animal models, and AI/ML modelling. As current drug development pipelines for traditional small molecules are not suited for these advanced therapies, this partnership will also create standardised tools and assays to screen new NATs, which will be available for researchers and regulators.
Dr Stefan Platz, SVP Clinical Pharmacology & Safety Sciences, AstraZeneca R&D said “This partnership brings together exceptional expertise in science, technology and data to address numerous challenges in NAT development. Together, we aim to set new standards in safety and innovation, driving meaningful progress for patients facing some of the most complex medical conditions.”
Dr Sara Wells, Director of the Mary Lyon Centre at MRC Harwell said “The use of multiple datasets, model systems and advanced analysis modalities is a key element of this exciting project, which couples the multidisciplinary team efforts to minimise the use of animals and wasteful repetition of experiments with the increased translatability of more predictive models and novel approaches to the design and testing of nucleic acid therapeutics. We are delighted to be part of this academia-industry partnership aimed at improving patient health. The Mary Lyon Centre also looks forward to playing its part in disseminating the great work of our colleagues to the biomedical community.”
Professor Owen Sansom, Director of the CRUK Scotland Institute, said “We are incredibly excited to be part of this groundbreaking MRC-funded initiative, providing our extensive expertise in the use of models to gain mechanistic insight on biological processes and adverse outcome pathways. Our aim is to make evidence-based predictions in the use of NATs to improve the likelihood of success for patients.”
Professor Eric Miska, Head of the Department of Biochemistry, University of Cambridge, said “I am incredibly excited to support this ground-breaking collaboration by connecting our fundamental nucleic acid research to industry and the clinic”.
Dr Glenn Wells, MRC Deputy Executive Chair, said: “This project is part of a £9 million public sector investment through MRC’s first Prosperity Partnerships. With additional contribution from industry and close collaboration with key regulatory bodies, we are addressing the safety and toxicity of advanced therapies. This research is critical to improving how gene, cell-based, and nucleic acid-dependent therapies are developed for conditions such as cancers and rare genetic disorders, so we can make meaningful improvements to patient outcomes.”
This industrial-academic partnership will be an essential part of advancing the NAT field, enabling faster translation of new therapies into the clinic and expansion to treat a wider range of diseases. The partnership will also train early career researchers and scientists to generate a skilled workforce and engage with patient groups at early stages of the project. Bringing together discovery and translational science through this academic-industrial partnership will enable the team to create safer and more effective treatments, improving outcomes for patients.
