Oxford and partners lead on two new MRC Centres to create cutting-edge gene therapies

The Medical Research Council (MRC), part of UKRI, is launching its first two Centres of Research Excellence (CoRE), which will develop transformative new advanced therapeutics for currently untreatable diseases. Oxford is leading one of these Centres and co-leading the other. Together, these international collaborations will receive up to £50 million each over 14 years.

The Centres will build on the huge progress that has been made in genomics - allowing the genetic basis of many diseases and processes to be identified - and advances in genome editing and other gene therapies, which have made it possible to develop treatments for previously incurable conditions.

The Centres will take different approaches to translating the advances in genomics into therapies to treat many diseases, such as heart disease, severe immune disorders, genetic causes of blindness, many developmental disorders that affect children, including those that cause severe seizures in babies, and neurodegenerative conditions including Huntingdon’s disease.

One centre, called the MRC/BHF Centre of Research Excellence in Advanced Cardiac Therapies, will be co-funded with the British Heart Foundation (BHF) and will focus on developing gene therapies for heart disease.

The other centre, called the MRC Centre of Research Excellence in Therapeutic Genomics, aims to make rare genetic disorders treatable by enabling the mass production of affordable cutting-edge gene therapies.

Oxford institutions involved in the new Centres include the Institute of Developmental and Regenerative Medicine (IDRM), the Department of Paediatrics, the Department of Physiology, Anatomy and Genetics (DPAG), the Nuffield Department of Clinical Neurosciences (NDCN) and the Radcliffe Department of Medicine.

The MRC’s new CoRE funding model aims to transform biomedical and health research by revolutionising approaches to prevention, early detection, diagnosis, and treatment of diseases by bringing together the very best researchers to tackle the challenge, wherever they are based. In addition, the Centres will be beacons of excellence driving positive changes in research culture, and in training the next generation of pioneers in the field.

MRC/BHF Centre of Research Excellence in Advanced Cardiac Therapies

The MRC/BHF CoRE in Advanced Cardiac Therapies aims to develop the first therapies to stimulate heart repair and regeneration in patients following a heart attack and in those with established heart failure, for which there are currently limited effective treatments.

Heart failure affects almost 1 million people in the UK and more than 65 million people around the world. Heart attacks are the main cause of heart failure because they cause loss of the heart muscle due to an interruption of the heart’s blood supply.

To treat heart failure, we need to develop innovative therapies that stimulate formation of new heart tissue, to compensate for that which is damaged or lost.

The researchers aim to discover and target key processes within the heart tissue, which can stimulate the proliferation of heart muscle cells, encourage the growth of new blood vessels, and counteract the formation of scars.

Many of these regenerative processes have been identified as occurring naturally in the hearts of other animals, including salamanders and fish, and even in human infants.

The Centre aims to develop the first therapies which can reawaken these regenerative processes within the cells of damaged human hearts.

They plan to do this using therapies based on nucleic acids – the building blocks of our genetic material DNA and RNA. These will include mRNA, similar to the cutting-edge techniques in the Covid-19 vaccines, and small regulatory RNAs. These will be identified through systematic, high throughput genetic screening.

The project will use viral and non-viral based technologies to deliver these therapeutic DNAs and RNAs into the cells of the heart. There they will alter the cell’s functions, for example to switch a function on or off, or to make a protein.

The researchers will work closely with the Cell and Gene Therapy Catapult and with industry, including AstraZeneca, AskBio and Batavia Biosciences, to collaborate on tasks, such as screening libraries for therapy targets and accessing gene therapy delivery technologies and with Syncona, a large venture capital firm in London, to drive further investment and progress toward application in patients.

Professor Paul Riley, a Co-director of the MRC/BHF Centre of Research Excellence in Advanced Cardiac Therapies, from the University of Oxford, said: 'To tackle heart disease, it’s critical that any therapy we develop needs to be globally applicable and affordable, so it can be rolled out at cost and imbedded in healthcare systems. Our goal is to bring one or more novel advanced therapies for heart failure to be ready for clinical trials in the first seven years of the programme.'

MRC Centre of Research Excellence in Therapeutic Genomics

The new MRC CoRE in Therapeutic Genomics aims to transform the diagnosis and treatment of genetic disorders by enabling the mass development of cutting-edge genetic therapies.

They aim to develop therapies for many devastating genetic disorders that are currently untreatable, such as rare disorders that cause severe seizures in infants and neurodevelopmental delay, certain types of blindness and immune disorders, and severe neurological disorders such as Huntington’s Disease.

Recent breakthroughs in genomics and the first generation of genetic therapies have begun to revolutionise the treatment of a few genetic disorders. However, the process to create, test, and approve each new therapy is too slow and expensive to enable treatments to be developed for the thousands of genetic disorders being diagnosed.

To overcome this, the Centre aims to develop processes to take successful genetic therapies and reprogramme them to treat new disorders. The new Centre will also use artificial intelligence approaches to enable scientists to process huge amounts of genetic data from patients at previously unimaginable depth.

Professor Stephan Sanders, Director of the new MRC CoRE in Therapeutic Genomics, from the University of Oxford, said: 'Reprogramming genetic therapies has the potential to treat thousands of genetic disorders. The new Centre will help create a paradigm shift in the knowledge, infrastructure, technology, and industry regulation so that we can make safe and effective patient-customised therapies en masse.'

Professor Deborah Gill, Co-Director of the MRC CoRE in Therapeutic Genomics, from the University of Oxford said: 'We will also prioritize innovation in research culture, ensuring that science is conducted in an ethical and responsible manner, incorporating feedback from patients and the public, so that the findings are distributed to benefit society. To achieve our vision, we will recruit talented researchers and students and teach them to consider every step of the way from lab to clinic.'

The Centre will work with UK and international partners, including Newcastle University, University College London (UCL), the Karolinska Institute (Sweden), and the University of California (Innovative Genomics Institute at UC Berkeley and UC San Francisco in the USA). The CoRE will also work in partnership with patient groups, clinicians, international consortia (N=1 Collaborative), industry (Danaher, Molecular Devices, IDT, Intellia, Bexorg, La Jolla Labs, the Jackson Laboratory, EveryONE Medicines), and UK infrastructure (Oxford-Harrington Rare Disease Centre, Rare Therapies Launch Pad, Genomics England, the Nucleic Acid Therapy Accelerator) to ensure that laboratory work translates into patient benefit.

The researchers will initially focus on developing genetic therapies for disorders of the blood, eye, and brain. The knowledge gained from treating these disorders will be shared widely, enabling these approaches to be extended to increasingly large numbers of disorders and organs by multiple research groups.

Delivering genetic therapies to the blood and eye has already led to clinical success. Blood cells can be extracted, edited, checked, and returned to the body where the ‘fixed’ cells can replicate, making blood-based immunity disorders a good initial target for genetic therapies.

In the eye, the retina is small, easily accessible by injection, and simple to examine, making it low-hanging fruit for treating cells without removing them from the body. The CoRE will focus on treating retinal blindness.

In contrast, while the brain is the organ most frequently affected by rare genetic disorders, delivering most therapies to the brain remains a challenge. The CoRE will initially focus on antisense oligonucleotides, which can already be delivered to cells in the brain, to treat severe neurological and neurodevelopmental disorders, for example, mutations in glutamate receptors (e.g. GRIN2A) or sodium channels (e.g. SCN2A) that can cause severe seizures in children. They will also develop new approaches to delivering genome-editing therapies to the brain.

Professor Patrick Chinnery, Executive Chair of the Medical Research Council, said: 'The MRC CoREs are a new way of funding bold and ambitious science that seeks to advance our ability to understand diseases, diagnose them at an early stage, intervene with new treatments and prevent diseases of the future. They will focus on bringing together the brightest scientists to tackle diseases of major medical importance, so that they will really change the landscape and improve the health of the nation.

'I am excited to see how the first two centres announced today will transform approaches in advanced therapeutics. We have seen the first green shoots of how advanced gene therapies could transform medicine, such as the mRNA Covid vaccines, or the recent announcement of the NHS approving a gene-editing therapy that could cure blood disorder thalassaemia. These two CoREs aim to bring these burgeoning technologies to mass fruition to treat many devastating diseases which will also lead to economic growth.'