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

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 g...

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Bibliographic Details
Published in:Molecular therapy 2018-01, Vol.26 (1), p.256-268
Main Authors: Le Meur, Guylène, Lebranchu, Pierre, Billaud, Fanny, Adjali, Oumeya, Schmitt, Sébastien, Bézieau, Stéphane, Péréon, Yann, Valabregue, Romain, Ivan, Catherine, Darmon, Christophe, Moullier, Philippe, Rolling, Fabienne, Weber, Michel
Format: Article
Language:English
Subjects:
AAV vector
Acuity
clinical trial
Cortex
Functional magnetic resonance imaging
Gene therapy
Genomes
Human health and pathology
Immunoglobulins
Immunology
Inflammation
inherited retinal dystrophies
Leber congenital amaurosis
Life Sciences
Lighting
Mutation
Nystagmus
Original
Patients
Photoreceptors
Questionnaires
Retina
Retinal degeneration
RPE65
Serotypes
Studies
Vectors (Biology)
Visual field
Visual pathways
Visual perception
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Summary: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. First results of a phase I/II clinical trial with an AAV serotype 4 vector in Leber congenital amaurosis associated with RPE65 gene deficiency are reported. The vector is well tolerated after subretinal injection. Efficacy parameters varied between patients during follow-up.
ISSN:1525-0016
1525-0024
DOI:10.1016/j.ymthe.2017.09.014