Oxford researchers awarded ARIA funding to develop transformative anti-viral therapies
Three innovative research projects aimed at transforming how we protect against respiratory viruses, led by teams at the University of Oxford, have secured funding through the UK’s Advanced Research and Invention Agency (ARIA).
University of Oxford researchers will lead three projects as part of ARIA’s Sustained Viral Resilience programme. Image credit: imaginima, Getty Images.
The projects are supported as part of ARIA’s Sustained Viral Resilience programme, a £57 million initiative led by Programme Director Brian Wang. In this programme, 11 funded teams will explore and unlock ways to create sustained innate immunoprophylactics (SIIPs) - a new class of medicines that provide durable, broad-spectrum protection against respiratory viruses by engineering the innate immune system.
Viruses are a large and diverse group of microorganisms, causing diseases that often affect the respiratory tract – ranging from the common cold to COVID-19 – and posing a continued risk of pandemic outbreaks. Viral infections also impose a substantial economic burden in the UK and worldwide, with the COVID-19 pandemic estimated to have cost the global economy more than £10tn.
The three successful projects at Oxford will be led by Mark Coles at the Kennedy Institute of Rheumatology in the Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS), Paul Klenerman at the Nuffield Department of Medicine (NDM) and Jan Rehwinkel at the MRC Weatherall Institute of Molecular Medicine (WIMM) in the Radcliffe Department of Medicine (RDM). These projects will draw on skills and expertise from collaborators across the University, and beyond, with Molly Stevens from the Department of Physiology, Anatomy and Genetics playing an important role in all three projects.
Developing "smart" DNA medicine to prevent respiratory infections
The iGATE project, led by Professor Mark Coles, aims to develop a new class of “smart” DNA medicines based on programmable synthetic biosensors. These biosensors are designed to remain inactive in healthy tissue but switch on in response to viral infection. The approach involves engineering compact gene “circuits” – inspired by how neural circuits process information – that can detect molecular signs of infection and activate targeted antiviral defences.
The project brings together researchers from across the University of Oxford, in collaboration with Professor Ron Weiss and Majo Duran at the Massachusetts Institute of Technology. By combining synthetic biology with artificial intelligence, the team will design and optimise gene circuits that can sense infection-related signals in respiratory cells and respond in a precise, controlled way. Importantly, these systems are intended to activate only when needed, reducing the risk of unnecessary inflammation while maintaining effective protection.
“The iGATE team combines world-leading expertise in bioengineering at MIT and respiratory infection research at the University of Oxford to develop a next-generation “smart” DNA medicine. This approach aims to strengthen early immune defences against both seasonal respiratory infections and emerging, unknown pandemic threats. If successful, it could offer a fundamentally new strategy for reducing the impact of future pandemics.”
The platform will use modular “plug-and-play” components, allowing different sensors and therapeutic effectors to be combined to address a range of viruses. The technology will be tested and refined in human airway models to ensure both safety and efficacy, with a strong emphasis on minimising unintended effects. In parallel, the team will develop delivery methods that introduce these DNA circuits without triggering unwanted immune responses.
Overall, iGATE aims to create a next-generation, self-regulating approach to strengthen the body’s early defences against respiratory infections and reduce the risk of severe disease and hospitalisation.
“We are delighted to develop advanced delivery technologies for the iGATE project and excited by the ambition and potential impact of the project.”
'Synthetic biology and immunology have each been advancing rapidly on their own. What excites us about this project is what happens when they truly intersect. For the first time, we can bring circuits with the modularity, specificity, and gradient-processing complexity that synthetic biology offers into the innate immune system. The line between a protective and a harmful innate immune response is very fine, and having the tools to intervene precisely is what draws us to this project,' said Majo Duran, a project co-lead at MIT.
Sustained protection through innate immune activation
Professor Jan Rehwinkel’s project will focus on harnessing MDA5, a key sensor in the innate immune system, to develop new prophylactic treatments capable of protecting against many different respiratory viruses.
The innate immune system is a complex network that protects against infections, including viruses. Previous discovery research by the Rehwinkel Group found that specialised proteins such as MDA5 have a key role in kick-starting the innate immune response – detecting viral or unusual RNA and triggering antiviral defences.
In this ARIA-funded project, researchers will design synthetic RNA molecules that activate MDA5, mimicking infection signals to stimulate a broad immune response. These RNA agonists will be delivered using DNA-based systems designed to target respiratory tissues.
The aim is to create a treatment that, after a single administration, could provide sustained protection against multiple respiratory viruses. The approach will be tested across cell models, human airway organoids and animal systems, against viruses such as influenza, SARS-CoV-2 and respiratory syncytial virus.
“We are deeply motivated by and excited about the unique possibilities ARIA funding unlocks to achieve a paradigm shift in the control of viral infections. The current clinical status quo – pathogen-specific vaccines and treatments – remains perpetually a step behind emerging threats, as evidenced by the recent SARS-CoV-2 pandemic. ARIA’s vision of sustained, broad-spectrum resilience is ambitious, yet we believe it is achievable by harnessing one of the very mechanisms that have protected our species through eons of viral evolution: the MDA5 pathway. By coupling this innate signalling pathway with cutting-edge synthetic biology and delivery engineering, we aim to build a prophylactic that we hope to be effective not just against known viruses, but also against those yet to emerge.”
MAGIC - harnessing unconventional T cells to provide broad immunity
The MAGIC consortium (MAIT activation to Generate Immune Control) is led by Paul Klenerman from the Nuffield Department of Medicine, together with Molly Stevens at DPAG, and a team of scientists from Birmingham, King’s College, London and Monash University in Melbourne (Del Besra, Patricia Barral and Jamie Rossjohn).
Mucosal-associated invariant T (MAIT) cells are the key target here, as these immune cells are known to respond to a range of different viruses and can provide protection against severe infection. The team have already shown that these cells can be boosted after exposure to small molecules usually made naturally by microbes.
This ARIA-funded project aims to find ways to boost MAIT cells in humans using synthetic molecules, which are stable and simple to deliver. Because MAIT cells have “memory” after boosting, and home to tissues such as the airways where they are most needed, the team hopes to provide longer lasting protection against a range of serious infections.
“We are excited to start the MAGIC project funded by ARIA, and to have the chance to translate our recent findings about unconventional T cells into a new type of preventive strategy. The team assembled are all experts in their field - it’s an amazing opportunity to bring them together to work on this one idea.”
Further information about the projects funded by ARIA’s Sustained Viral Resilience programme can be found on the ARIA website.
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