Mechanism of cone cells death in retinitis pigmentosa

Abstract

AbstractRetinitis pigmentosa (RP) is a group of diseases in which one of a large number of mutations causes death of rod photoreceptors. After rods die, cone photoreceptors slowly degenerate in a characteristic pattern. Rod cell death causes night blindness, but visual disability and blindness result from cone degeneration and therefore it is critical to determine the mechanisms by which it occurs. The death of rods reduces oxygen consumption resulting high tissue levels of oxygen in the outer retina. The excess oxygen stimulates superoxide radical production by mismatches in the electron transport chain in mitochondria and by stimulation of NADPH oxidase activity in cytoplasm. The high levels of superoxide radicals overwhelm the antioxidant defense system and generate more reactive species including peroxynitrite which is extremely damaging and difficult to detoxify. This results in progressive oxidative damage in cones which contributes to cone cell death and loss of function because drugs or gene transfer that reduce oxidative stress promote cone survival and maintenance of function. Oral administration of N‐acetylcysteine (NAC) has shown good efficacy in mouse models of RP prompting the FIGHT RP1 open label clinical trial, the results of which will be presented.