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‘The Retina UK Gene Team’

Prof Robin Ali (King’s College London), Prof James Bainbridge (UCL), Prof Michel Michaelides (UCL)

For the last ten years, this team of world-leading experts have been steadily developing a pipeline of gene therapies for several forms of early-onset inherited retinal conditions. Thanks to their work, four of these potential treatments have moved into early phase clinical trials, sponsored by biotechnology company MeiraGTx, with a fifth soon to follow. The team has also treated a small number of infants with a rare and severe form of Leber congenital amaurosis (LCA4), under a special license at Great Ormond Street Hospital.

UK Inherited Retinal Dystrophy Consortium (‘RP Genome Project’)

Prof Alison Hardcastle (UCL), Prof Graeme Black (Manchester), Prof Susie Downes (Oxford), Prof Chris Inglehearn (Leeds)

This unique and highly collaborative project brought together four of the largest research groups in the UK specialising in inherited retinal conditions. The team set out to investigate cases where the underlying genetic fault could not be identified.

By gathering and analysing genetic data from hundreds of people, including those who took part in the UK 100,000 Genomes Project, the group has identified seven novel disease-causing genes, established comprehensive understanding of the role of nine further genes, and helped discover a brand new disease mechanism. Most importantly, the project has provided answers and choices for over 100 individuals and their families, and helped establish improved diagnosis for the future.

Non-viral gene therapy for Usher syndrome

Prof Mariya Moosajee (UCL/The Francis Crick Institute)

‘Traditional’ gene therapy uses viruses to carry the therapeutic genes. This recently completed project explored an alternative approach, by developing a special DNA structure to act as a gene packaging system. This “S/MAR vector” has the capacity to hold much larger genes such as the Usher syndrome gene USH2A, which cannot fit inside a virus. The new vector may also have some safety advantages.

Prof Moosajee has demonstrated that the S/MAR vector can work well to restore healthy USH2A in zebrafish and cell-based disease models. This provides a springboard to further development of this potential therapy, not only for Usher syndrome but also for other retinal conditions involving large genes, such as Stargardt disease.

Finding hidden faults in the ABCA4 gene in Stargardt disease

Prof Frans Cremers (RadmoudUMC, The Netherlands)

Faults in the ABCA4 gene cause Stargardt disease, the most common cause of childhood-onset retinal degeneration. However, in many cases of apparent Stargardt disease, scientists have struggled to get a clear genetic diagnosis because they have been unable to find any faults in the parts of the ABCA4 gene that directly provide instructions for building protein.

Thanks to support from Retina UK, Prof Cremers and his talented team have overcome this problem by designing a very cost-effective method of scanning the entire gene, even those sections known as introns, which do not code for protein-building ingredients but nonetheless play a key role in influencing the construction of healthy protein. They have discovered 70 previously hidden genetic faults, significantly improving understanding of the underlying mechanisms of disease.

They have also made this new test available for free to ophthalmologists and researchers across Europe, so that many more families can get clear answers.

Understanding the role of splicing and the PRPF31 gene in autosomal dominant RP, and moving towards gene therapy

Prof Majlinda Lako (Newcastle University)

RP is commonly caused by a fault in a group of genes that regulate the editing of unwanted passages out of a set of genetic instructions, a process known as splicing. The PRPF31 gene is a key member of this group.

Using specially developed cell-based models, derived from the skin cells of people living with PRPF31-associated RP, Prof Lako and her team were able to significantly expand understanding of the knock-on effects of faulty splicing on retinal cells.

This work has provided a springboard to a new project, for which Retina UK has just awarded funding, so that Prof Lako can look at developing a gene therapy to treat PRPF31-related RP. This is a great example of how establishing a disease model and understanding disease mechanisms can lead to therapy development.

PhD Studentships – building the research workforce of the future

We are very proud to have collaborated with the Macular Society in launching promising young scientists into a career in inherited sight loss research. A PhD is an essential first step in a research career, and involves the student undertaking a supervised project that not only produces useful outcomes but also provides the necessary scientific training and development. We are currently funding, Elena Piotter, who is at Oxford University investigating the efficacy and safety of potential gene editing approaches for the treatment of Stargardt disease. This could also be relevant to a number of other inherited retinal conditions.