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Mol Ther. 2018 Jan 3;26(1):256-268. doi: 10.1016/j.ymthe.2017.09.014. Epub 2017 Sep 19.

Safety and Long-Term Efficacy of AAV4 Gene Therapy in Patients with RPE65 Leber Congenital Amaurosis.

Author information

1
Ophthalmology Department, University Hospital Centre (CHU) de Nantes, Nantes, France; INSERM UMR 1089, University of Nantes, CHU de Nantes, Nantes France. Electronic address: guylene.lemeur@univ-nantes.fr.
2
Ophthalmology Department, University Hospital Centre (CHU) de Nantes, Nantes, France; UMR 6597 CNRS, Image and Video Communication Team, Institute for Research into Communications and Cybernetics of Nantes, Polytech Nantes, Nantes, France.
3
Ophthalmology Department, University Hospital Centre (CHU) de Nantes, Nantes, France.
4
INSERM UMR 1089, University of Nantes, CHU de Nantes, Nantes France.
5
Department of Genetics, CHU de Nantes, Nantes, France.
6
Reference Centre for Neuromuscular Disorders, FILNEMUS, CHU de Nantes, Nantes, France.
7
Institut du Cerveau et de la Moelle épinière ICM, Centre for NeuroImaging Research (CENIR), Paris, France.
8
Ophthalmology Department, University Hospital Centre (CHU) de Nantes, Nantes, France; INSERM UMR 1089, University of Nantes, CHU de Nantes, Nantes France.

Abstract

The aim of this study was the evaluation of the safety and efficacy of unilateral subretinal injection of the adeno-associated vector (AAV) serotypes 2 and 4 (AAV2/4) RPE65-RPE65 vector in patients with Leber congenital amaurosis (LCA) associated with RPE65 gene deficiency. We evaluated ocular and general tolerance and visual function up to 1 year after vector administration in the most severely affected eye in nine patients with retinal degeneration associated with mutations in the RPE65 gene. Patients received either low (1.22 × 1010 to 2 × 1010 vector genomes [vg]) or high (between 3.27 × 1010 and 4.8 × 1010 vg) vector doses. An ancillary study, in which six of the original nine patients participated, extended the follow-up period to 2-3.5 years. All patients showed good ophthalmological and general tolerance to the rAAV2/4-RPE65-RPE65 vector. We observed a trend toward improved visual acuity in patients with nystagmus, stabilization and improvement of the visual field, and cortical activation along visual pathways during fMRI analysis. OCT analysis after vector administration revealed no retinal thinning, except in cases of macular detachment. Our findings show that the rAAV2/4.RPE65.RPE65 vector was well tolerated in nine patients with RPE65-associated LCA. Efficacy parameters varied between patients during follow-up.

KEYWORDS:

AAV vector; RPE65; clinical trial; gene therapy; inherited retinal dystrophies

PMID:
29033008
PMCID:
PMC5763029
DOI:
10.1016/j.ymthe.2017.09.014
[Indexed for MEDLINE]
Free PMC Article

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