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- Title
Safety of Recombinant Adeno-Associated Virus Type 2–RPE65 Vector Delivered by Ocular Subretinal Injection.
- Authors
Jacobson, Samuel G.; Acland, Gregory M.; Aguirre, Gustavo D.; Aleman, Tomas S.; Schwartz, Sharon B.; Cideciyan, Artur V.; Zeiss, Caroline J.; Komaromy, Andras M.; Kaushal, Shalesh; Roman, Alejandro J.; Windsor, Elizabeth A.M.; Sumaroka, Alexander; Pearce-Kelling, Susan E.; Conlon, Thomas J.; Chiodo, Vincent A.; Boye, Sanford L.; Flotte, Terence R.; Maguire, Albert M.; Bennett, Jean; Hauswirth, William W.
- Abstract
AAV2 delivery of the RPE65 gene to the retina of blind RPE65-deficient animals restores vision. This strategy is being considered for human trials in RPE65-associated Leber congenital amaurosis (LCA), but toxicity and dose efficacy have not been defined. We studied ocular delivery of AAV-2/2.RPE65 in RPE65-mutant dogs. There was no systemic toxicity. Ocular examinations showed mild or moderate inflammation that resolved over 3 months. Retinal histopathology indicated that traumatic lesions from the injection were common, but thinning within the injection region occurred only at the two highest vector doses. Biodistribution studies at 3 months postinjection showed no vector in optic nerve or visual centers in the brain and only isolated non-dose-related detection in other organs. We also performed biodistribution studies in normal rats at about 2 weeks and 2 months postinjection and vector was not widespread outside the injected eye. Dose–response results in RPE65-mutant dogs indicated that the highest 1.5-log unit range of vector doses proved efficacious. The efficacy and toxicity limits defined in this study lead to suggestions for the design of a subretinal AAV-2/2.RPE65 human trial of RPE65-associated LCA.Molecular Therapy (2006) 13, 1074–1084; doi: 10.1016/j.ymthe.2006.03.005
- Publication
Molecular Therapy, 2006, Vol 13, Issue 6, p1074
- ISSN
1525-0016
- Publication type
Academic Journal
- DOI
10.1016/j.ymthe.2006.03.005