Retinoid isomerohydrolase RPE65 has received a tremendous amount of attention due to successful clinical gene therapy for Leber congenital amaurosis (LCA) cases caused by RPE65 mutations.
The form of hereditary childhood blindness Leber congenital amaurosis (LCA) caused by biallelic RPE65 mutations is considered treatable with a gene therapy product approved in the US and Europe.
RPE65-associated Leber congenital amaurosis (LCA) is one of highly heterogeneous, early onset, severe retinal dystrophies with at least 130 gene mutation sites identified.
In particular, the first gene therapy bioproduct for RPE65-associated Leber's congenital amaurosis, which was approved by the US Food and Drug Administration in 2017, has provided tremendous encouragement to the field of gene therapy.
Ocular gene therapy with recombinant adeno-associated virus (AAV) has shown vector-mediated gene augmentation to be safe and efficacious in the retina in one set of diseases (retinitis pigmentosa and Leber congenital amaurosis (LCA) caused by RPE65 deficiency), with excellent safety profiles to date and potential for efficacy in several additional diseases.
Suppression of TH signaling with antithyroid drug treatment or by targeting iodothyronine deiodinases and TH receptors preserves cones in mouse models of retinal degeneration, including the Leber congenital amaurosisRpe65-deficient mice.
Among many clinical trials of gene therapy for hereditary retinal diseases, a phase 3 clinical trial of voretigene neparvovec (AAV2-hRPE65v2, Luxturna) recently showed significant efficacy for RPE65-mediated inherited retinal dystrophy including Leber congenital amaurosis and RP.
The blonde fundus in such cases may exhibit phenotypic overlap and shared therapeutic implications with other aggressive chorioretinal dystrophies such as end-stage choroideremia, gyrate atrophy, or RPE65-Leber congenital amaurosis.
Various blinding conditions in humans, such as Leber congenital amaurosis and retinitis pigmentosa (RP), are attributed to either homozygous or compound heterozygous mutations in RPE65.
In the present study, we assessed the potentially deleterious effects of long-term expression of these optogenes on the diseased retina in a large animal model of retinal degeneration, the RPE65-deficient Briard dog model of Leber congenital amaurosis.
Leber congenital amaurosis (LCA) is a visual disease which is caused by RPE65 mutations and results in retinal degeneration and severe vision loss in early infancy.
Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial.
Safety and durability of effect of contralateral-eye administration of AAV2 gene therapy in patients with childhood-onset blindness caused by RPE65 mutations: a follow-on phase 1 trial.