Long-term Safety and Efficacy of Aav-mediated Gene Transfer to the Retina of Patients Affected With Leber’s Congenital Amaurosis Due to Rpe65 Mutations

Abstract

Purpose: : We and others have recently reported on preliminary safety and efficacy results following rAAV2-RPE65 delivery to the retina of patients with Leber’s congenital amaurosis (LCA) due to RPE65 mutations. In our initial report (NEJM, 2008 May 22;358(21):2240-8) we have shown absence of toxicity and serious adverse events in the presence of significant improvement of visual function for up to 5 months after gene delivery in 3 LCA patients. The goal of the present study was to analyze the effect of gene transfer in these patients for up to 13.5 months after vector administration.

Methods: : Three LCA patients bearing RPE65 mutations received unilateral subretinal injections with 1.5x10e10 particles of AAV2-hRPE65v2. Standard tests of visual acuity, Goldmann visual field examination, mobility testing, pupillometry, nystagmus recording and optical coherence tomography were used to assess safety and efficacy of gene transfer for up to 13.5 months.

Results: : There was no evidence of adverse effects of gene transfer on retinal function and there was no evidence of systemic toxicity in this long-term study. The significant improvement of visual function previously reported at the 5 month timepoint was maintained over the course of the study.

Conclusions: : rAAV2 delivery to the retina of LCA patients with RPE65 mutations appears safe and results in stable improvement in retinal/visual function after a single vector application.The first two authors contributed equally to this abstract; The last three names are co-corresponding authors.Acknowledgements: All members of the CHOP-Penn-TIGEM-SUN LCA-RPE65 team, Center for Cellular and Molecular Therapeutics (CCMT) at The Children’s Hospital of Philadelphia (CHOP); Foundation Fighting Blindness (FFB), Howard Hughes Medical Institute (HHMI), F.M. Kirby Foundation, Scheie Eye Institute, RPB, the Mackall Foundation Trust.

Clinical Trial: : www.clinicaltrials.gov NCT00516477 LCARPE

Keywords: retinal degenerations: hereditary • gene transfer/gene therapy • clinical (human) or epidemiologic studies: outcomes/complications