Towards a new drug therapy for age-related macular degeneration

Why is this research needed?

Age related macular degeneration (AMD) is the leading cause of severe and permanent sight loss in the UK, and in the developed world. This progressive disease damages the macular: the part of the eye that is responsible for our central, detailed, and much of our colour vision. A poor understanding of exactly what causes the macula to become damaged means that AMD is currently incurable and, for the most part, untreatable.

Dr Shu’s project focused on one of the major early indicators of AMD, to determine whether treating it can halt the progress of disease in patients, and save their sight from deteriorating.

Project background

In the early stages of AMD, fatty deposits build up between layers in the retina known as the retinal pigment epithelium (RPE) and Bruch’s membrane. The RPE is a single layer of highly pigmented cells that performs many critical functions, including supporting retinal photoreceptors, which convert light into signals that are sent to the brain, enabling us to see. Bruch’s membrane lies underneath the RPE. The fatty deposits, known as drusen, which accumulate between these layers, can also build up between the RPE and the photoreceptors.

Drusen contain a variety of fatty substances, including cholesterol, which damages the RPE and contributes to the development of AMD. The source of the cholesterol is thought to come from photopigment-containing discs, found in the photoreceptor cells. In a healthily functioning retina, the RPE cells break down and digest these discs. It is thought that excess cholesterol should move from the RPE into the Bruch’s membrane, from where it is returned to the liver through a process called reverse cholesterol transport (RCT), before being excreted as bile. It is further supposed that fatty deposits found in the retinas of people with AMD could be due to dysfunctional RCT, especially as several RCT-related genes have been shown to be predictive risk factors for AMD.

What was the aim of the project?

Dr Shu’s team had already discovered that a protein called TSPO is involved in promoting cholesterol removal from RPE cells. Furthermore, if the gene that produces TSPO is missing, the removal of cholesterol is significantly decreased, resulting in an accumulation of deposits inside the RPE cells.

With our funding, Dr Shu set out to explore whether drugs designed to target the gene that produces TSPO could stimulate the removal of cholesterol from RPE cells, and so stop fatty deposits forming.

What was the outcome?

Dr Shu's team identified five drugs that were shown to aid cholesterol removal and reduce inflammation damage in human RPE cells, and to alleviate symptoms of AMD in mice. This suggests that TSPO-targeted therapy could be a promising new avenue to explore in the treatment of AMD.

Further information

You can find more about the causes and symptoms of AMD here.