title: Gene therapy for Leber's congenital amaurosis is safe and effective through 1.5 years after vector administration.
abstract: The safety and efficacy of gene therapy for inherited retinal diseases is being tested in humans affected with Leber's congenital amaurosis (LCA), an autosomal recessive blinding disease. Three independent studies have provided evidence that the subretinal administration of adeno-associated viral (AAV) vectors encoding RPE65 in patients affected with LCA2 due to mutations in the RPE65 gene, is safe and, in some cases, results in efficacy. We evaluated the long-term safety and efficacy (global effects on retinal/visual function) resulting from subretinal administration of AAV2-hRPE65v2. Both the safety and the efficacy noted at early timepoints persist through at least 1.5 years after injection in the three LCA2 patients enrolled in the low dose cohort of our trial. A transient rise in neutralizing antibodies to AAV capsid was observed but there was no humoral response to RPE65 protein. The persistence of functional amelioration suggests that AAV-mediated gene transfer to the human retina does not elicit immunological responses which cause significant loss of transduced cells. The persistence of physiologic effect supports the possibility that gene therapy may influence LCA2 disease progression. The safety of the intervention and the stability of the improvement in visual and retinal function in these subjects support the use of AAV-mediated gene augmentation therapy for treatment of inherited retinal diseases.
authors: Department of Ophthalmology, Second University of Naples, Naples, Italy. franctes@tin.it
authors: Francesca
authors: F
authors: Simonelli
authors: Albert M
authors: AM
authors: Maguire
authors: Francesco
authors: F
authors: Testa
authors: Eric A
authors: EA
authors: Pierce
authors: Federico
authors: F
authors: Mingozzi
authors: Jeannette L
authors: JL
authors: Bennicelli
authors: Settimio
authors: S
authors: Rossi
authors: Kathleen
authors: K
authors: Marshall
authors: Sandro
authors: S
authors: Banfi
authors: Enrico M
authors: EM
authors: Surace
authors: Junwei
authors: J
authors: Sun
authors: T Michael
authors: TM
authors: Redmond
authors: Xiaosong
authors: X
authors: Zhu
authors: Kenneth S
authors: KS
authors: Shindler
authors: Gui-Shuang
authors: GS
authors: Ying
authors: Carmela
authors: C
authors: Ziviello
authors: Carmela
authors: C
authors: Acerra
authors: J Fraser
authors: JF
authors: Wright
authors: Jennifer Wellman
authors: JW
authors: McDonnell
authors: Katherine A
authors: KA
authors: High
authors: Jean
authors: J
authors: Bennett
authors: Alberto
authors: A
authors: Auricchio
mesh_terms: D000328:Adult; D002352:Carrier Proteins / Q000235:genetics*; D000229:Dependovirus / Q000235:genetics; D018450:Disease Progression; D005136:Eye Proteins / Q000235:genetics*; D005500:Follow-Up Studies; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D006801:Humans; D057130:Leber Congenital Amaurosis / Q000235:genetics* / Q000628:therapy*; D008957:Models, Genetic; D012160:Retina / Q000378:metabolism; D013997:Time Factors; D019076:Transgenes; D016896:Treatment Outcome; 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