title: Treatment of leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial.
abstract: Leber congenital amaurosis (LCA) is a group of autosomal recessive blinding retinal diseases that are incurable. One molecular form is caused by mutations in the RPE65 (retinal pigment epithelium-specific 65-kDa) gene. A recombinant adeno-associated virus serotype 2 (rAAV2) vector, altered to carry the human RPE65 gene (rAAV2-CBSB-hRPE65), restored vision in animal models with RPE65 deficiency. A clinical trial was designed to assess the safety of rAAV2-CBSB-hRPE65 in subjects with RPE65-LCA. Three young adults (ages 21-24 years) with RPE65-LCA received a uniocular subretinal injection of 5.96 x 10(10) vector genomes in 150 microl and were studied with follow-up examinations for 90 days. Ocular safety, the primary outcome, was assessed by clinical eye examination. Visual function was measured by visual acuity and dark-adapted full-field sensitivity testing (FST); central retinal structure was monitored by optical coherence tomography (OCT). Neither vector-related serious adverse events nor systemic toxicities were detected. Visual acuity was not significantly different from baseline; one patient showed retinal thinning at the fovea by OCT. All patients self-reported increased visual sensitivity in the study eye compared with their control eye, especially noticeable under reduced ambient light conditions. The dark-adapted FST results were compared between baseline and 30-90 days after treatment. For study eyes, sensitivity increases from mean baseline were highly significant (p < 0.001); whereas, for control eyes, sensitivity changes were not significant (p = 0.99). Comparisons are drawn between the present work and two other studies of ocular gene therapy for RPE65-LCA that were carried out contemporaneously and reported.
authors.affiliation: Department of Ophthalmology, University of Florida, Gainesville, FL 32610, USA.
authors.forename: William W
authors.initials: WW
authors.lastname: Hauswirth
authors.forename: Tomas S
authors.initials: TS
authors.lastname: Aleman
authors.forename: Shalesh
authors.initials: S
authors.lastname: Kaushal
authors.forename: Artur V
authors.initials: AV
authors.lastname: Cideciyan
authors.forename: Sharon B
authors.initials: SB
authors.lastname: Schwartz
authors.forename: Lili
authors.initials: L
authors.lastname: Wang
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Conlon
authors.forename: Sanford L
authors.initials: SL
authors.lastname: Boye
authors.forename: Terence R
authors.initials: TR
authors.lastname: Flotte
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Byrne
authors.forename: Samuel G
authors.initials: SG
authors.lastname: Jacobson
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001766:Blindness / Q000151:congenital / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D003623:Dark Adaptation; D000229:Dependovirus; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005500:Follow-Up Studies; D030342:Genetic Diseases, Inborn / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D009154:Mutation; D012160:Retina / Q000378:metabolism; D014785:Vision, Ocular; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase
chemical_list: D002352:Carrier Proteins; D005136:Eye Proteins; D019745:cis-trans-Isomerases; D000099178:Retinoid Isomerohydrolase
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