Leber congenital amaurosis (LCA) is an inherited, genetically heterogeneous form of retinal dystrophy that usually presents as blindness or severely impaired vision at birth or during the first few months of life. Among the 3,000 patients with LCA in the United States, approximately 8 to 10% are caused by mutations in a gene encoding a retinal pigment epithelium-specific 65 kDa (RPE65) protein. RPE65 protein is the retinoid isomerase required for conversion of all-trans-retinyl ester to 11-cis-retinol in the visual cycle that mediates phototransduction. Patients with RPE65-associated LCA have profound impairment of photoreceptor function as indicated by a nondetectable electroretinogram (ERG) but with relatively preserved photoreceptor structure and an intact visual cortex that is responsive to high intensity light stimulation. No treatment for LCA is currently available, but subretinal delivery of recombinant adeno-associated virus (rAAV) vectors expressing RPE65 has demonstrated substantial restoration of visual function in mouse and dog models of RPE65-associated blindness, and initial clinical trials in small numbers of patients has been encouraging.
The specific aim of this research proposal is to support a Phase 1/2 clinical trial that will complement the previously reported Phase 1 clinical trials, by using a larger volume of rAAV2-CB-hRPE65 to treat a larger area of the retina in patients with Leber congenital amaurosis caused by mutations in the RPE65 gene. In this Phase 1/2 clinical trial, 12 subjects (6 who are e18 years of age and 6 who are 8-17 years of age) will receive a single 450 ?L subretinal injection of rAAV2-CB-hRPE65 at one of two dosage levels. Safety will be monitored by evaluation of ocular and non-ocular adverse events, hematology and clinical chemistry parameters, and presence of the vector in blood. Efficacy will be measured by evaluation of visual fields, visual acuity and electroretinography.

Public Health Relevance

Leber congenital amaurosis (LCA) is an inherited form of retinal disease that usually presents as blindness or severely impaired vision at birth or during the first few months of life. Approximately 300 patients in the United States have LCA caused by mutations in the RPE65 gene. No treatment for LCA is currently available. This project will evaluate a novel, RPE65 gene therapy product for treatment of LCA in a clinical trial.

National Institute of Health (NIH)
Food and Drug Administration (FDA)
Research Project (R01)
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Special Emphasis Panel (ZFD1-OPD-N (01))
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Applied Genetic Technologies Corporation
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Weleber, Richard G; Pennesi, Mark E; Wilson, David J et al. (2016) Results at 2 Years after Gene Therapy for RPE65-Deficient Leber Congenital Amaurosis and Severe Early-Childhood-Onset Retinal Dystrophy. Ophthalmology 123:1606-20