Dataset Information

Analysis of a large choroideremia dataset does not suggest a preference for inclusion of certain genotypes in future trials of gene therapy.

ABSTRACT: Choroideremia (CHM) is an X-linked degeneration of the retinal pigment epithelium, photoreceptors, and choroid, which causes nyctalopia and progressive constriction of visual fields leading to blindness. The CHM gene encodes Rab escort protein 1 (REP-1). In this work, we reviewed the phenotypes and genotypes of affected males with the purpose of understanding the functional effects of CHM mutations and their relationship with the phenotypes.A retrospective review of 128 affected males was performed analyzing the onset of symptoms, visual acuity, and visual fields with respect to their mutations in the CHM gene.In rank order, reflecting data from this report, the most common mutations found in the CHM gene were nonsense mutations (41%), exon deletions (37%), and splice sites (14%) associated with a loss of functional protein. In the pool of 106 CHM mutations, we discovered four novel missense mutations (c.238C>T; p.L80F, c.819G>T; p.Q273H, c.1327A>G; p.M443V, and c.1370C>T; p.L457P) predicted to be severe changes affecting protein stability and folding with the effect similar to that of other types of mutations. No significant genotype-phenotype correlation was found with respect to the onset of nyctalopia, the onset of other visual symptoms, visual acuity, or width of visual fields.There is no evidence to support exclusion of CHM patients from clinical trials based on their genotypes or any potential genotype-phenotype correlations.

SUBMITTER: Freund PR

PROVIDER: S-EPMC4867567 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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Analysis of a large choroideremia dataset does not suggest a preference for inclusion of certain genotypes in future trials of gene therapy.

Freund Paul R PR Sergeev Yuri V YV MacDonald Ian M IM

Molecular genetics & genomic medicine 20160228 3

<h4>Background</h4>Choroideremia (CHM) is an X-linked degeneration of the retinal pigment epithelium, photoreceptors, and choroid, which causes nyctalopia and progressive constriction of visual fields leading to blindness. The CHM gene encodes Rab escort protein 1 (REP-1). In this work, we reviewed the phenotypes and genotypes of affected males with the purpose of understanding the functional effects of CHM mutations and their relationship with the phenotypes.<h4>Methods</h4>A retrospective revi ...[more]

PMID: 27247961

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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

Analysis of a large choroideremia dataset does not suggest a preference for inclusion of certain genotypes in future trials of gene therapy.

Publications

Analysis of a large choroideremia dataset does not suggest a preference for inclusion of certain genotypes in future trials of gene therapy.

Similar Datasets

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