- University of Sheffield spinout company, Crucible Therapeutics, will develop therapies for MND and FTD cases with the C9orf72 gene mutation
- Sheffield's pioneering research could pave the way for future clinical trials for one of the most common forms of these incurable neurodegenerative diseases
- There are approximately 1,500 and 2,000 new MND and FTD cases per year respectively but there is no effective treatment available
MND is a neurodegenerative disease which causes nerve cells to progressively stop working throughout the spinal cord and the brain. The disease, which predominantly affects people aged 60-65, leads to progressive paralysis and death usually within three to six years from the onset of symptoms.
FTD involves the degeneration of frontal and temporal lobes of the brain causing altered personality features. It most commonly affects people aged 45-65 and can affect behaviour, personality, language and movement. There is currently no effective treatment for MND or for FTD.
Crucible Therapeutics was developed based on research from three leading experts in the internationally renowned Neuroscience Institute at the University of Sheffield. The collaborative team consists of Professor Guillaume Hautbergue, Professor of Translational RNA Biology, Professor Mimoun Azzouz, Chair of Translational Neuroscience and Professor Dame Pamela Shaw, Professor of Neurology and Director of the Sheffield Institute for Translational Neuroscience (SITraN).
Professor Guillaume Hautbergue, Director of Crucible Therapeutics, led the development of earlier research funded by the MND Association. Working alongside Professor Dame Pamela Shaw and Professor Mimoun Azzouz, the team identified a particular protein called SRSF1 which binds to the pathological repeated RNA molecules and transports them out of the cell centre, effectively overriding the gatekeeping machinery within the nucleus by opening a back door. The researchers have further shown that by reducing the SRSF1 protein or altering its makeup so that it is unable to interact with the cell's export machinery, it is possible to reduce the amount of rogue RNA molecules escaping into the cell's cytoplasm.
Building on this research, the team have developed a pioneering gene therapy technology aimed at interacting with the SRSF1 pathway to bring about a therapeutic effect in MND and FTD patients.
Following the demonstration of the mechanism of action of SRSF1 and further proof of concept work, the Cell and Gene Therapy Catapult (CGT Catapult) provided translational development support to the programme through medicines development planning, analytical method development and preclinical safety testing advice. Alongside this collaboration between The University of Sheffield and CGT Catapult, further research at Sheffield into the development and testing of the gene therapy was funded by LifeArc and the MND Association, through the LifeArc Philanthropic Fund.
Crucible is receiving financing and support from Northern Gritstone and Argobio Studio to fund essential development and manufacturing work, which will take the company up to its first clinical trial.
It is the first spinout focusing on advanced therapeutics to receive investment from Northern Gritstone, the investment business focused on university spinouts and technology-enabled businesses in the North of England. Argobio Studio is a pan-European biotech company start-up vehicle whose experienced team of entrepreneurs and scientific directors has supported multiple advanced therapeutics start-ups across Europe since inception. Demonstrating its ongoing commitment, Argobio Studio continues to offer operational guidance to Crucible throughout its spinout phase and will persist in providing support during the upcoming preclinical development stage.
Neill Moray Mackenzie and Jonathan Foley from Argobio Studio will support the development of the company's novel therapies. Together their considerable R&D, commercial and manufacturing experience in multiple gene therapy companies will be brought to bear at this critical time for Crucible. Professor Guillaume Hautbergue will join them as Non-Executive Director on the board of Crucible Therapeutics representing the founders.
Professor Guillaume Hautbergue, Founding Director of Crucible Therapeutics, Professor of Translational RNA Biology at the University of Sheffield, said: "I worked on the therapeutic target for more than 15 years, initially to study its roles from a discovery perspective, prior to realising its promising potential for the development of a novel gene therapeutics in close collaboration with the other founders. What an incredible journey! I feel blessed and honoured to be working with them and moving forward a bench discovery onto the translational path. I am now delighted to continue our preclinical development programme in partnership with Argobio Studio and Northern Gritstone who bring very significant levels of expertise and support."
Professor Mimoun Azzouz, Co-Founder of Crucible Therapeutics, Professor and Chair of Translational Neuroscience at the University of Sheffield, Founder and Director of Gene Therapy Innovation and Manufacturing Centre (GTIMC), said: "I am delighted with the support received today from Northern Gritstone and Argobio Studio. Crucible Therapeutics is a great addition to the favourable and dynamic gene therapy ecosystem at the University of Sheffield. This is a massive deliverable which would enable the progress of the translational pipeline being developed by the company towards potential life-changing therapies for patients with MND and FTD."
Professor Dame Pamela Shaw, Co-Founder of Crucible Therapeutics, Professor of Neurology at the University of Sheffield and Director of the Sheffield Institute for Translational Neuroscience (SITraN), said: "Our novel therapeutic approach has made significant strides in our pursuit of transforming how these devastating diseases are treated and potentially achieving meaningful therapeutic impact. Today marks an important milestone, which brings us closer to supplying transformative treatments to people with neurological diseases like MND and FTD. The significant experience and support that Northern Gritstone and Argobio Studio bring to Crucible further enables our pre-clinical development while allowing us to strategically build our team."
Duncan Johnson, CEO of Northern Gritstone, said: "I'm pleased to say that the Crucible's founders, Professors Dame Pamela Shaw, Guillaume Hautbergue and Mimoun Azzouz, exemplify the world-leading research and medical expertise already present in the North of England and we look forward to working with them as they prepare to bring Crucible's therapeutic candidate closer to clinical trials. We also welcome the opportunity to invest alongside the team at Argobio Studio whose invaluable experience in gene therapy will be critical as Crucible takes the first important step in its journey."
Neill Moray Mackenzie, Entrepreneur in Residence, Partner at Argobio Studio, said: "Ever since I had tea with Stephen Hawking in Cambridge many years ago, I have been searching for a realistic hope of a cure for this devastating disease out of respect for him. At Argobio Studio, we have the opportunity at looking all the technologies with unbiased view and I can honestly say the Sheffield approach was the most compelling for us. While the therapy is still in early stages of development, we look forward to working alongside Northern Gritstone to bring the programme to fruition."
