Visual Acuity after Retinal Gene Therapy for Choroideremia

Edwards, Thomas L.; Jolly, Jasleen K; Groppe, Markus; Barnard, Alun R.; Cottriall, Charles L.; Tolmachova, Tanya; Black, Graeme C M; Webster, Andrew R.; Lotery, Andrew; Holder, Graham E.; Xue, Kanmin; Downes, Susan M.; Simunovic, Matthew P.; Seabra, Miguel C.; MacLaren, Robert E.

doi:10.1056/nejmc1509501

Cited by 181 publications

(150 citation statements)

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“…18–23 This, combined with the low rate of patients in whom sequencing failed to identify a genetic cause, reaffirms the logic of a gene-replacement strategy as a possible means of treatment, such as that currently undertaken at our center. 6,7 …”

Section: Discussionmentioning

confidence: 99%

“…Finally, we also sought to determine the prevalence of presumed null mutations and the rate of detection of mutations by sequencing. Both of these latter issues are especially important in assessing the potential suitability of gene therapy via a “gene replacement” strategy, a potential treatment that currently is under investigation by our group (ClinicalTrials.gov number, NCT01461213) 6,7 and by others (ClinicalTrials.gov numbers, NCT02077361, NCT02341807).…”

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confidence: 99%

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The Spectrum of CHM Gene Mutations in Choroideremia and Their Relationship to Clinical Phenotype

Simunovic

Jolly

Xue

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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PurposeWe report the underlying genotype and explore possible genotypic-phenotypic correlations in a large cohort of choroideremia patients.MethodsWe studied prospectively a cohort of 79 patients diagnosed within a tertiary referral service for patients with retinal dystrophies. Phenotypic evaluation consisted of clinical examination, including visual acuity and residual retinal area by fundus autofluorescence (FAF). Genotype was established by sequencing. We also investigated whether particular genotypes were associated with more severe phenotypes by performing analysis of covariance (ANCOVA), with visual acuity and FAF as the dependent variables and age as the covariant.ResultsA total of 74 (94%) of patients in our cohort had causative mutations by sequencing, the majority of which were anticipated to be null. Of these, 35 (47%) had insertions and deletions, 13 (18%) had mutations predicted to affect splicing, and 26 (35%) had single point mutations. In the latter case, 13 of 21 (62%) pedigrees with single point mutations were C to T transitions at C-phosphate-G (CpG) dinucleotides. These mutations were spread across 5 of only 24 CpG dinucleotides in the entire CHM cDNA. Furthermore, these 5 locations are the only sites at which C to T transitions result in a stop codon. No clear evidence was found for genotype–phenotype correlation except in the instance of a patient with a large deletion involving neighbouring sequences.ConclusionsIn patients with a diagnosis of choroideremia made by a specialty service, there is a high likelihood of establishing a genetic diagnosis. The majority of causative mutations appear to be null and, therefore, may benefit from gene replacement therapy. A disproportionate number of single point mutations observed were C to T transitions, consistent with the evolutionary decay of CpG dinucleotides through methylation and subsequent deamination. Hence, the development of choroideremia in such patients may represent the unwanted consequence of human evolution; de novo mutations are predicted to arise at these sites in future generations. (ClinicalTrials.gov number, NCT01461213.)

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

The Spectrum of CHM Gene Mutations in Choroideremia and Their Relationship to Clinical Phenotype

Simunovic

Jolly

Xue

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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“…Keywords: retinitis pigmentosa, monkey, whole-exome analysis R ecently, the clinical efficacy of gene therapy [1][2][3][4] and regenerative medicine 5,6 for intractable ocular diseases, including inherited retinal degeneration (IRD) has been reported. Studies evaluating the mechanisms of disease pathogenesis, as well as the efficacy of these new therapeutic treatments, have typically used rodent disease models.…”

Section: Discussionmentioning

confidence: 99%

Discovery of a Cynomolgus Monkey Family With Retinitis Pigmentosa

Ikeda

Nishiguchi

Miya

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. To accelerate the development of new therapies, an inherited retinal degeneration model in a nonhuman primate would be useful to confirm the efficacy in preclinical studies. In this study, we describe the discovery of retinitis pigmentosa in a cynomolgus monkey (Macaca fascicularis) pedigree.METHODS. First, screening with fundus photography was performed on 1443 monkeys at the Tsukuba Primate Research Center. Ophthalmic examinations, such as indirect ophthalmoscopy, ERGs using RETeval, and optic coherent tomography (OCT) measurement, were then performed to confirm diagnosis. RESULTS.Retinal degeneration with cystoid macular edema was observed in both eyes of one 14-year-old female monkey. In her examinations, the full-field ERGs were nonrecordable and the outer layer of the retina in the parafoveal area was not visible on OCT imaging. Moreover, less frequent pigmentary retinal anomalies also were observed in her 3-year-old nephew. His full-field ERGs were almost nonrecordable and the outer layer was not visible in the peripheral retina. His father was her cousin (the son of her mother's older brother) and his mother was her younger half-sibling sister with a different father.CONCLUSIONS. The hereditary nature is highly probable (autosomal recessive inheritance suspected). However, whole-exome analysis performed identified no pathogenic mutations in these monkeys.

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“…Change in BCVA were accompanied by an improvement in scotopic microperimetry. At 3.5 years after treatment (Edwards et al 2016), BCVA in the two patients with advanced disease had improved by 21 and 18 letters from their baseline measurements, while BCVA in their untreated fellow eyes decreased by 18 and 6 letters, respectively. In addition to the MacLaren study, there are four ongoing clinical trials of gene therapy in patients with CHM (NCT02077361, NCT02553135, NCT02671539, and NCT02341807).…”

Section: Choroideremia Gene Therapymentioning

confidence: 91%