Identifying novel therapies for inherited eye disease

Brief Lay Background

The inherited retinal dystrophies (IRDs) are the leading cause of visual loss in children and adults of working age. Mutations in over 150 genes lead to death of the light sensing photoreceptor cells at the back of the eye, causing untreatable blindness. Whilst gene therapy has brought the field hope, genes must be targeted one at a time and so it will take many years for this technology to be developed for the rarer genes. There is a requirement for treatments that are effective for all IRDs, regardless of genetic cause.

It is possible that mutations in multiple genes all result in a common final pathway of photoreceptor death that could be a target for therapy. Therefore, a better understanding of how photoreceptors die is a crucial area of research if we are to develop multiple approaches to treating the IRDs.

What problem/knowledge gap does it help address

The inherited retinal dystrophies (IRDs) are the leading cause of visual loss in children and working adults. In 2019 alone they cost £523.3m in economic and well-being costs in the UK.

Currently, only one gene therapy treatment is available for one rare form of disease and all published trials to date show the visual improvement is minimal and short lived. Though this has given the field hope, and should lead to gene therapies targeting other alleles being trialed and licenced, there is a need for complementary therapies which prevent photoreceptor death that can be used in combination, alongside gene therapies, and also, in rarer forms of disease where the specific gene has not been targeted.

This project aims to define the mechanism(s) that lead to photoreceptor cell death in IRDs by assessing disruption of autophagy flux and the molecular networks unregulated in stressed and dying photoreceptors in the team’s genetic models of IRDs. Further, it will assess the capacity of cell death inhibitors to prevent photoreceptor death and improve retinal function. By doing so, the team aim to identify therapeutic targets that can be brought forward for biosafety and drug delivery studies and, eventually, clinical trials. This study is therefore incredibly important for patients affected by genetic eye disease and their families, for clinicians who care for these patients and the UK taxpayer in general.

Aim of the research project

To investigate the mechanisms that cause photoreceptor death and lead to IRDs.

Key procedures/objectives

1. Determine the extent to which Autophagy is disrupted in IRDs.
2. Fully define the changes in cell networks that drive photoreceptor death in IRDs.
3. Seek to use inhibitors of cell death, already in clinical trials, to prevent photoreceptor death and preserve vision.

Potential impact on people with sight loss

At present there is only one gene therapy treatment available for a very rare form of IRD. If the team are able to identify the cell death pathway responsible for photoreceptor loss in IRDs, and identify a drug to stop this, it would be taking a large step towards the development of a novel treatment for IRDs.