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Pathogenic mechanisms and the prospect of gene therapy for choroideremia.

ABSTRACT: INTRODUCTION:Choroideremia is a rare, X-linked disorder recognized by its specific ocular phenotype as a progressive degenerative retinopathy resulting in blindness. New therapeutic approaches, primarily based on genetic mechanisms, have emerged that aim to prevent the progressive vision loss. AREAS COVERED:This article will review the research that has progressed incrementally over the past two decades from mapping to gene discovery, uncovering the presumed mechanisms triggering the retinopathy to preclinical testing of potential therapies. EXPERT OPINION:While still in an evaluative phase, the introduction of gene replacement as a potential therapy has been greeted with great enthusiasm by patients, advocacy groups and the medical community.

SUBMITTER: Dimopoulos IS

PROVIDER: S-EPMC4522943 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Pathogenic mechanisms and the prospect of gene therapy for choroideremia.

Dimopoulos Ioannis S IS Chan Stephanie S MacLaren Robert E RE MacDonald Ian M IM

Expert opinion on orphan drugs 20150701 7

<h4>Introduction</h4>Choroideremia is a rare, X-linked disorder recognized by its specific ocular phenotype as a progressive degenerative retinopathy resulting in blindness. New therapeutic approaches, primarily based on genetic mechanisms, have emerged that aim to prevent the progressive vision loss.<h4>Areas covered</h4>This article will review the research that has progressed incrementally over the past two decades from mapping to gene discovery, uncovering the presumed mechanisms triggering ...[more]

PMID: 26251765

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Project description:Background and objectives: Choroideremia (CHM) is an X-linked recessive chorioretinal dystrophy caused by mutations involving the CHM gene. Gene therapy has entered late-phase clinical trials, although there have been variable results. This review gives a summary on the outcomes of phase I/II CHM gene therapy trials and describes other potential experimental therapies. Materials and Methods: A Medline (National Library of Medicine, Bethesda, MD, USA) search was performed to identify all articles describing gene therapy treatments available for CHM. Results: Five phase I/II clinical trials that reported subretinal injection of adeno-associated virus Rab escort protein 1 (AAV2.REP1) vector in CHM patients were included. The Oxford study (NCT01461213) included 14 patients; a median gain of 5.5 ± 6.8 SD (-6 min, 18 max) early treatment diabetic retinopathy study (ETDRS) letters was reported. The Tubingen study (NCT02671539) included six patients; only one patient had an improvement of 17 ETDRS letters. The Alberta study (NCT02077361) enrolled six patients, and it reported a minimal vision change, except for one patient who gained 15 ETDRS letters. Six patients were enrolled in the Miami trial (NCT02553135), which reported a median gain of 2 ± 4 SD (-1 min, 10 max) ETDRS letters. The Philadelphia study (NCT02341807) included 10 patients; best corrected visual acuity (BCVA) returned to baseline in all by one-year follow-up, but one patient had -17 ETDRS letters from baseline. Overall, 40 patients were enrolled in trials, and 34 had 2 years of follow-up, with a median gain of 1.5 ± 7.2 SD (-14 min, 18 max) in ETDRS letters. Conclusions: The primary endpoint, BCVA following gene therapy in CHM, showed a marginal improvement with variability between trials. Optimizing surgical technique and pre-, peri-, and post-operative management with immunosuppressants to minimize any adverse ocular inflammatory events could lead to reduced incidence of complications. The ideal therapeutic window needs to be addressed to ensure that the necessary cell types are adequately transduced, minimizing viral toxicity, to prolong long-term transgenic potential. Long-term efficacy will be addressed by ongoing studies.

Dataset Information

Pathogenic mechanisms and the prospect of gene therapy for choroideremia.

Publications

Pathogenic mechanisms and the prospect of gene therapy for choroideremia.

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