Promotion of RPE cholesterol removal: a new therapeutic strategy for age-related macular degeneration

Age-related macular degeneration (AMD) is the most common cause of severe visual impairment in the elderly population in the Western world. In the UK the number with sight loss due to AMD is expected to rise from 223,224 in 2010 to 291,982 by 2020.

The major clinical feature is the presence of deposits built up between retinal layers called the retinal pigment epithelium (RPE) and Bruch’s membrane (a thin membrane underneath RPE cells). The deposits can also occur between the light sensitive cells (photoreceptors) and the RPE. Pathological analyses show that these deposits contain a variety of lipids (‘fat’), including cholesterol, the source of which is thought be the photopigment-containing discs in the photoreceptors. As part of their normal function of retinal maintenance, RPE cells break down and digest these discs. It is thought that these lipids should move from the RPE into Bruch’s membrane and return to the liver through reverse cholesterol transport (RCT), which serves to return excess cellular cholesterol to the liver for excretion in bile. Abnormal deposit formation in AMD retinas may therefore be due to dysfunctional RCT: several RCT-related genes are predictive risk factors for AMD.

Our recent data demonstrated that a protein called ‘TSPO’ is involved in promoting cholesterol removal from RPE cells. If the gene producing the TSPO protein is missing, cholesterol efflux is significantly decreased in RPE cells, resulting in accumulation of cholesterol inside the cells. The level of TSPO protein is decreased in mouse RPE and retina during ageing, as is the cholesterol removal process. In this project we will identify specific TSPO targeted compounds (‘drugs’), which can promote the removal of cholesterol from the RPE.

We will then examine whether these compounds can suppress formation of lipid deposits underneath the RPE in an AMD mouse model. The project will develop new therapies to treat patients at an early stage, this halting progression of AMD.