Mechanisms of cell death in choroideremia

Brief Lay Background

Choroideremia is a rare inherited eye disorder that predominantly affects men.

It causes the gradual breakdown of important components of the retina. This includes photoreceptors (the cells within the eyes that respond to light), the pigment cells that support them, and a layer of capillaries that provides the retina’s blood supply, called the choroid.

People with choroideremia experience progressive loss of vision from an early age, and often completely lose their vision by adulthood, 20-30 years after their symptoms began.

What problem/knowledge gap does it help address

Choroideremia is caused by faults in a single gene known as CHM. Professor Seabra’s team was the first to develop a gene therapy that can correct this fault and has the potential to treat patients with choroideremia.

However, although the treatment showed promise in clinical trials, its success relies on retinal cells carrying the replacement gene staying alive. Unfortunately, because choroideremia causes these cells to degenerate, the benefit of gene therapy is only short-term. Treatments that can be used alongside gene therapy to prevent this degeneration are therefore needed. However, scientists currently know little about how retinal cells die in choroideremia. If they can understand more about these degeneration processes, they can develop drugs to stop them.

Aim of the research project

The aim of this project is to explore the different ways that retinal cells die in choroideremia.

Key procedures/objectives

1. Develop laboratory models of choroideremia using cells from people with choroideremia. These cells will be grown in the lab alongside healthy retinal cells with and without the CHM mutation.
2. Use the new models to study how cells die in choroideremia. Two different types of cell death will be explored. One is apoptosis, the mechanism cells trigger to kill themselves off if they are damaged or no longer needed. The second mechanism is necroptosis, is a type of self-destruction cells use when apoptosis is otherwise prevented. The study will look for hallmarks of both these processes in the models of CHM.
3. The third aim is to look at the release of exosomes in the models. Exosomes are small parcels that all cells make and use to carry information to other cells. There is evidence that retinal cells do not release exosomes properly in choroideremia, and that this might promote necroptosis.  

Potential impact on people with sight loss

If successful, this project will provide a foundation of knowledge that researchers can use to develop treatments to protect retinal cells from dying in people with choroideremia. There are already drugs available that work by preventing necroptosis, so if retinal cell death uses the same mechanism, these treatments could be repurposed in choroideremia. When used alongside gene therapy, it is hoped that these could prevent sight loss in people with choroideremia.