Investigation of LW/MW cone opsin disease and therapy in retinal organoids

Brief Lay Background

In normal colour vision, the eye can see all three primary colours – red, blue and green. This is made possible by cone-shaped cells called photoreceptors that detect different wavelengths of light. Cone photoreceptors contain proteins called ‘opsins’ that are responsible for converting light into signals that are sent to the brain.

Everyone has differences in the genes that code for opsins, but some people inherit genetic faults (mutations) that can inactivate cone photoreceptors. Mutations that affect a single type of cone photoreceptor cause conditions such as two-colour vision, and red-green colour blindness. Some people inherit faults in opsin genes that affect two types of photoreceptors, and this causes more severe sight problems where people are unable to distinguish colour, lose the sharpness of their vision and experience discomfort in bright light.

What problem/knowledge gap does it help address

Professor Hardcastle’s team has identified a genetic mechanism that could lead to faulty cone photoreceptors. It involves the combined effects of small genetic changes known as single-nucleotide polymorphisms (SNPs). These cause photoreceptor cells to ‘skip’ part of the opsin gene when they make opsin protein. Each SNP on its own does not appear to be harmful, but the team think that in combination they prevent normal development of cone photoreceptors and lead to disease.

The work to identify this mechanism used cell extracts. To build on this, in this project the PhD student will develop models of the human retina called ‘organoids’ that carry these characteristic SNPs. Organoids are tiny, three-dimensional groups of cells grown from human stem cells.

This is an important next step to study the mechanism of disease and test potential treatments as a first step towards clinical trials.

Aim of the research project

To investigate a genetic fault that causes colour blindness (a severe retinal disease), aiming to determine how much of the gene is faulty and when this fault occurs.

Key procedures/objectives

1. Test the hypothesis that the group of SNPs cause gene skipping in the human retina by studying human 3D retinal organoids.
2. Explore the potential of a gene editing technique as a treatment to suppress gene skipping in organoids.
3. Investigate whether the location of opsin genes relative to a genetic ‘control panel’ influences which genes are switched on and off.

This award will also contribute to building capacity in eye research as it will lead to a PhD for an early career researcher.

Potential impact on people with sight loss

If successful, this project could quickly lead to clinical trials of a potential new treatment for people with inherited colour blindness.

Around 4 in 10 people with inherited retinal diseases are thought to have this specific gene-skipping fault. If this fault could be suppressed with the gene editing technique, it could slow down disease progression and prevent sight loss.