Retinoid isomerohydrolase RPE65 (RPE65) (RPE65)

Retinoid isomerohydrolase RPE65 (RPE65) is a 65 kDa enzyme located in the retinal pigment epithelium that is essential for the regeneration of visual pigments (UniProt: P43897). It catalyzes the rate-limiting step of the visual cycle by converting all-trans-retinyl esters into 11-cis-retinol, which is a precursor to the chromophore 11-cis-retinal (PubMed: 16041375). This chromophore binds to opsin to form rhodopsin, the light-sensitive pigment in rod and cone photoreceptors required for vision (StatPearls: NBK545233). Mutations in the RPE65 gene lead to a lack of 11-cis-retinal, causing severe inherited retinal dystrophies such as Leber congenital amaurosis type 2 (LCA2) and retinitis pigmentosa type 20 (RP20) (NIH Gene: 6121). RPE65 is the target of voretigene neparvovec-rzyl, the first FDA-approved gene therapy, which delivers a functional copy of the gene to restore the visual cycle (FDA: BL 125610). Additionally, small molecule inhibitors like emixustat have been studied to slow the visual cycle and reduce the accumulation of toxic lipofuscin in conditions like geographic atrophy (PubMed: 27553135).

Other names

Retinal pigment epithelium-specific 65 kDa proteinAll-trans-retinyl-palmitate hydrolaseRetinol isomeraseLCA2RP20mRPE65

Voretigene neparvovec acts via gene replacement to provide a functional RPE65 enzyme; emixustat acts as a small molecule inhibitor of RPE65 to slow the visual cycle and reduce toxic byproduct accumulation (FDA: BL 125610; PubMed: 27553135).