Major step forward as new approach to rare disease drug development yields first research results.

A team of scientists and business professionals at Queen Mary University of London have made a significant step towards overcoming the difficulties of developing drugs for epidermolysis bullosa (EB, a rare skin disease) and other rare diseases.

Developing disease modifying therapies for rare diseases is extremely challenging. It’s clinically difficult due to the small cohort sizes, and it’s difficult to raise investment as the market may not be big enough to cover the costs. The average cost of developing a new drug in 2024 was over $2bn.

A lack of pre-clinical disease models is a major bottleneck. A new initiative by Queen Mary University of London and DEBRA-Research to address this has now yielded its first research results.  

 

Providing pre-clinical rare disease models as a service

Pre-clinical models are lab-based stand-ins for a human disease, which scientists use to study the condition and test potential treatments before they can be safely trialled in people.

Dr Emanuel Rognoni, a senior lecturer at Queen Mary University of London, explains:

“Making accurate pre-clinical models is expensive and slow. For common diseases we already have well-established models and decades of published data to work from. Little of this exists for rare diseases, so if you’re a scientist trying to develop a drug for EB you first need to create a preclinical model before you can even get started on your research. But now you can use ours. This will significantly reduce the time it takes to do drug development research.”

Dr Emanuel Rognoni and Dr Matthew Caley, with the backing of DEBRA Research, are developing TREAT-EB, a pipeline of pre-clinical models for EB at Queen Mary’s Blizard Institute, which can be used for academic and commercial testing of promising drugs. “Pre-clinical models as a service” is an established business model for common diseases but severely lacking for rare diseases and completely absent for EB.

The newly published research, a GOSH Charity-funded study into the potential of targeting TGFβ signalling (a method by which cells communicate), is the first example of the team’s TREAT-EB pre-clinical pipeline. It comes less than a year into the initiative, thereby demonstrating the business model’s potential to fast-track development of new EB therapies.

Dr Rognoni and Dr Caley found that targeting TGFβ signalling with the small molecule inhibitor RepSox significantly improves skin health and regeneration in mice. Their results are published in EMBO Molecular Medicine.

The study also included Queen Mary researchers funded by DEBRA UK and Barts Charity, who together make up the Epidermolysis Bullosa Research Hub at Queen Mary University of London.

 

Why disrupting harmful signalling crosstalk is important in EB

EB is a group of rare and incredibly painful genetic skin conditions that cause the skin to blister and tear at the slightest touch. With skin as fragile as a butterfly’s wings, EB is often referred to as ‘butterfly skin’. It is thought to affect at least 5,000 people in the UK and 500,000 worldwide, mostly children. There is currently no cure.

Our skin contains multiple types of fibroblasts, specialist cells which build and maintain the structure that keeps skin tissue strong, flexible, and able to self-repair.

Dr Rognoni and Dr Caley discovered that papillary fibroblasts, the type which live just under the skin’s surface, are unusually abundant in skin damaged by EB.

Dr Caley, a senior lecturer at Queen Mary University of London, explains:

“When healthy skin gets damaged, our papillary fibroblasts promote healing by telling cells in the outer layer of the skin to produce αvβ6 integrin, a protein which activates TGFβ to heal wounds. Too many of these fibroblasts means too much TGFβ signalling, which worsens the excessive blistering and highly fragile skin already associated with EB. By inhibiting the TGFβ using RepSox, we were able to improve skin healing and reduce symptoms of the disease.”

 

A hopeful future for tackling rare diseases

The technique is a treatment not a cure. EB occurs when proteins like laminin‑332 fail to hold the skin layers together, targeting TGFβ with RepSox doesn’t correct this, and the research has only been done in mice, so a clinical drug remains a long way off.

Nonetheless, Dr Rognoni and Dr Caley’s research represents a significant endorsement of the “Pre-clinical rare disease models as a service” business model being developed by Queen Mary University of London's Business Development team, which the university is looking to expand upon. It’s hoped the approach could be replicated across other rare diseases which have similar research bottlenecks.

Aoife Regan, Director of Impact and Charitable Programmes at GOSH Charity said:

 “Children living with rare conditions like epidermolysis bullosa deserve effective treatments, and we're proud to have supported this research which has uncovered a promising new way to improve skin health in EB. This exciting discovery not only advances our understanding of the disease but also offers new hope that better treatments could one day improve the lives of children and families affected by EB.”