RPE65 (retinoid isomerohydrolase) is a critical enzyme in the retinoid visual cycle that catalyzes the cleavage and isomerization of all-trans-retinyl esters to 11-cis-retinol, which is subsequently oxidized to 11-cis-retinal, the essential chr1 for rod and cone photoreceptors 1. RPE65 exists in both soluble and membrane-bound forms, where the membrane form binds all-trans-retinyl esters and the soluble form binds vitamin A, facilitating the complete visual cycle through interactions with LRAT 2. Additionally, RPE65 catalyzes carotenoid isomerization, converting lutein to meso-zeaxanthin, an eye-specific antioxidant 3. Mutations in RPE65 cause Leber congenital amaurosis (LCA) type 2, characterized by early-onset progressive rod-cone dystrophy leading to severe visual impairment or blindness 4. RPE65 mutations also cause retinitis pigmentosa types 20 and 87, accounting for approximately 2-5% of retinitis pigmentosa cases 5. RPE65-mediated inherited retinal dystrophies are now clinically significant due to successful gene replacement therapy. Voretigene neparvovec (AAV2-hRPE65v2) demonstrated both safety and efficacy in phase 3 trials, improving functional vision in previously untreatable RPE65-mediated disease, with 65% of treated patients achieving maximum functional improvement at one year 67.