Mutations in RPE65, a gene essential to normal operation of the visual (retinoid) cycle, cause the childhood blindness known as Leber congenital amaurosis (LCA).
The gene therapy voretigene neparvovec (VN) is the first Food and Drug Administration-approved treatment for vision loss owing to the ultra-rare RPE65-mediated inherited retinal disorders.
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.
Leber congenital amaurosis (LCA) associated with retinal pigment epithelium-specific protein 65 kDa (RPE65) mutations is a severe hereditary blindness resulting from both dysfunction and degeneration of photoreceptors.
Demonstration of safe and stable reversal of blindness after a single unilateral subretinal injection of a recombinant adeno-associated virus (AAV) carrying the RPE65 gene (AAV2-hRPE65v2) prompted us to determine whether it was possible to obtain additional benefit through a second administration of the AAV vector to the contralateral eye.
Mutations in human RPE65 cause Leber's congenital amaurosis and other forms of autosomal recessive retinitis pigmentosa which are associated with early-onset blindness.
Mutations in the retinal pigment epithelium gene encoding RPE65 cause an early onset autosomal recessive form of human retinitis pigmentosa, known as Leber congenital amaurosis (LCA), which results in blindness or severely impaired vision in children.
Recent clinical trials using recombinant adeno-associated virus serotype 2 (rAAV2) successfully reversed blindness in patients with LCA caused by RPE65 mutations after one subretinal injection.
These preclinical studies have already allowed the field to reach the point where gene therapy to treat inherited blindness has been brought to clinical trial.In this chapter, we focus on AAV-mediated specific gene therapy for inherited retinal degenerative diseases, describing the disease targets, the preclinical studies in animal models and the recent success of the LCA-RPE65 clinical trials.
The RPE65 mutations Y368H and IVS1 + 5g-->a present in compound heterozygous form cause severe visual compromise in childhood and progress to nearly total vision loss by the second to third decades of life.
Mutations in key transcription factors SOX2 and P63 were linked with developmental defects and postnatal abnormalities such as corneal opacification, neovascularization, and blindness.
Following a gene candidate approach, we established that RPE65, the isomerohydrolase of the visual cycle, is responsible for severe childhood blindness (Leber congenital amaurosis or early onset retinal dystrophy).
Mutations in RPE65, a gene essential to normal operation of the visual (retinoid) cycle, cause the childhood blindness known as Leber congenital amaurosis (LCA).