Dataset Information

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

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.

SUBMITTER: Le Meur G

PROVIDER: S-EPMC5763029 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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

Le Meur Guylène G Lebranchu Pierre P Billaud Fanny F Adjali Oumeya O Schmitt Sébastien S Bézieau Stéphane S Péréon Yann Y Valabregue Romain R Ivan Catherine C Darmon Christophe C Moullier Philippe P Rolling Fabienne F Weber Michel M

Molecular therapy : the journal of the American Society of Gene Therapy 20170919 1

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. ...[more]

PMID: 29033008

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Project description:BackgroundLeber congenital amaurosis (LCA) is a congenital retinal dystrophy that results in significant and often severe vision loss at an early age. Comprehensive analysis of the genetic mutations and phenotypic correlations in LCA patients has allowed for significant improvements in understanding molecular pathways of photoreceptor degeneration and dysfunction. The purpose of this article is to review the literature on the subject of retinal gene therapy for LCA, including historical descriptions, preclinical animal studies, and human clinical trials.MethodsA literature search of peer-reviewed and indexed publications from 1996-2011 using the PubMed search engine was performed. Key terms included "Leber congenital amaurosis", LCA, RPE65, "cone-rod dystrophy", "gene therapy", and "human trials" in various combinations. Seminal articles prior to 1996 were selected from primary sources and reviews from the initial search. Articles were chosen based on pertinence to clinical, genetic, and therapeutic topics reviewed in this manuscript. Fundus photographs from LCA patients were obtained retrospectively from the clinical practice of one of the authors (R.A.S).ResultsHerein, we reviewed the literature on LCA as a genetic disease, the results of human gene therapy trials to date, and possible future directions towards treating inherited retinal diseases at the genetic level. Original descriptions of LCA by Theodor Leber and subsequent research demonstrate the severity of this disease with early-onset blindness. Discoveries of the causative heritable mutations revealed genes and protein products involved in photoreceptor development and visual transduction. Animal models have provided a means to test novel therapeutic strategies, namely gene therapy. Stemming from these experiments, three independent clinical trials tested the safety of subretinal delivery of viral gene therapy to patients with mutations in the RPE65 gene. More recently, efficacy studies have been conducted with encouraging results.ConclusionsInitial safety studies indicated promising results of subretinal delivery of viral vector with subclinical immunologic or surgical sequelae. Overall, these initial studies demonstrate that viral vector gene therapy results are very promising, safe, and effective. Future studies measuring potential improvement in photoreceptor function may rely on recent advances in retinal imaging and electrophysiologic testing.

Dataset Information

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

Publications

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

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