Retinoid isomerohydrolase (RPE65) (RPE65)

Retinoid isomerohydrolase (RPE65) is a 65 kDa enzyme primarily expressed in the retinal pigment epithelium (RPE) that is essential for the regeneration of the visual chromophore 11-cis-retinal [7, 9]. It functions as an isomerohydrolase, converting all-trans-retinyl esters into 11-cis-retinol, which is then oxidized and transported to photoreceptors to enable light perception [22]. Mutations in the RPE65 gene disrupt this visual cycle, leading to severe inherited retinal dystrophies such as Leber congenital amaurosis type 2 (LCA2) and retinitis pigmentosa type 20 (RP20), which typically result in childhood blindness [10, 12]. RPE65 is the target of voretigene neparvovec (Luxturna), the first FDA-approved gene therapy for a genetic disease, which utilizes an adeno-associated virus to deliver a functional copy of the gene to the RPE [6, 13]. Small molecule inhibitors like emixustat have also been developed to modulate the visual cycle and reduce the accumulation of toxic retinoid byproducts in diseases like age-related macular degeneration [1, 4]. Therapeutic challenges include the surgical risks of subretinal injection and the potential for long-term retinal atrophy despite initial functional gains [19, 24].

Other names

Retinal pigment epithelium-specific 65 kDa proteinAll-trans-retinyl-palmitate hydrolaseMeso-zeaxanthin isomeraseRetinol isomeraseLutein isomeraseLCA2RP20

Gene augmentation therapy (delivery of a functional RPE65 gene copy to restore protein expression in the retinal pigment epithelium); Visual cycle modulation (competitive inhibition of isomerohydrolase activity to slow the regeneration of 11-cis-retinal and reduce toxic byproduct accumulation).