Choroideremia: molecular mechanisms and development of AAV gene therapy

Patrício, Maria I.; Barnard, Alun R.; Xue, Kanmin; MacLaren, Robert E.

doi:10.1080/14712598.2018.1484448

Cited by 30 publications

(40 citation statements)

References 100 publications

(195 reference statements)

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“…Choroideremia is an inherited chorioretinal dystrophy for which clinical trials of gene therapy are ongoing. [20][21][22][23][24] The molecular and clinical findings in the current case provide strong evidence that c.1359C>T (p.(Gln451Phefs*3)) in the CHM gene should be considered a disease-causing variant. Moreover, patients with this variant should be considered as candidates for future CHM-related therapies.…”

Section: Discussionmentioning

confidence: 58%

Synonymous Variant in the CHM Gene Causes Aberrant Splicing in Choroideremia

Palma

Motta

Gomes

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Choroideremia is an inherited retinal degeneration caused by 280 different pathogenic variants in the CHM gene. Only one silent/synonymous variant (c.1359C>T; p.(Ser453=)) has been reported and was classified as inconclusive based on in silico analysis. This study elucidates the pathogenicity of this variant also found in a Brazilian patient. METHODS. Ophthalmological examinations such as color fundus photography, spectraldomain optical coherence tomography, fundus autofluorescence, and macular integrity assessment microperimetry were performed. The subjects' total RNA was extracted from peripheral blood cells. cDNA was synthesized and the amplification between exon 10 and 14 of the CHM mRNA was performed. The amplification products were sequenced by Sanger sequencing and the results were aligned to the reference sequence. RESULTS. The synonymous variant c.1359C>T p.(Ser453=) in the CHM gene is associated with an error in mRNA processing, leading preferentially to production of an aberrant transcript without exon 11 (p.(Gln451Phefs*3)). This anomalous mRNA production is related to typical choroideremia phenotype. CONCLUSIONS. These molecular findings reinforce the need for more detailed investigation of silent variants in patients with well-defined phenotype of retinal dystrophies. Molecular and clinical findings provided evidence that c.1359C>T (p.(Gln451Phefs*3)) in CHM should be considered a disease-causing variant.

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Section: Discussionmentioning

confidence: 58%

Synonymous Variant in the CHM Gene Causes Aberrant Splicing in Choroideremia

Palma

Motta

Gomes

et al. 2020

Invest. Ophthalmol. Vis. Sci.

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“…Measured with two different methods, the area of RPE in the central macula was seen to decrease significantly (P < 0.001) at a rate of 2.5 to 2.9 mm 2 annually, and at a percentage of 8.1% to 8.9%. Considering an average of six measurements done by two graders using Photoshop, the area of RPE measured from 64 eyes was seen to decrease significantly (P < 0.001) at a rate of 2.57 ± 3.22 mm 2 annually, and percentage of 8.39% ± 5.24%. The data measured by grader 1 using Photoshop were normalized (i.e., setting both the mean and SD of the data to 1) and plotted ( Supplementary Fig.…”

Section: General Comparison Between Two Methodsmentioning

confidence: 95%

“…1 All mutations in CHM result in the truncation or absence of the normal protein product REP1, and this makes CHM a prime candidate for gene replacement therapy. 2 Clinical trials of experimental therapies for inherited retinal therapies are challenging us to seek accurate outcome measures that will predict safety and efficacy. In previously reported trials of CHM gene therapy, ETDRS (Early Treatment Diabetic Retinopathy Study) letter acuity was used as a primary end point.…”

Section: Introductionmentioning

confidence: 99%

Quantification of RPE Changes in Choroideremia Using a Photoshop-Based Method

Zhai

Dimopoulos

et al. 2020

Trans. Vis. Sci. Tech.

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To develop a reliable and efficient method for quantifying the area of preserved retinal pigment epithelium (RPE), facilitating the evaluation of disease progression or response to therapy in choroideremia (CHM). Methods: The fundus autofluorescence images of CHM patients were captured at baseline and 1 year. A Photoshop-based method was developed to allow the reliable measurement of the RPE area. The results were compared with measurements generated by the Heidelberg Eye Explorer 2 (HEYEX2). The areas measured by two independent graders were compared to assess the test-retest reliability. Results: By using the Photoshop-based method, the area of the RPE measured from 64 eyes was seen to decrease significantly (P < 0.001) at a rate of 2.57 ± 3.22 mm 2 annually, and a percentage of 8.39% ± 5.24%. The average standard deviations for Photoshop were less than that for HEYEX2 (0.5-1.1 in grader 1; 0.4-1.6 in grader 2), indicating less intragrader variability. The RPE decrease as determined by the Photoshop-based method showed excellent reliability with an intraclass correlation coefficient of 0.944 (95% confidence interval, 0.907-0.966). In Bland-Altman plots, the Photoshop method also exhibited better intergrader agreement. Conclusions: Photoshop-based quantification of preserved RPE area in patients with CHM is feasible and has better test-retest reliability compared with the HEYEX2 method. Translational Relevance: An accurate quantification method for longitudinal RPE change in CHM patients is an important tool for the evaluation of efficacy in any therapeutic trials.

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“…For conditions for which the existing treatment only delays the progression of the symptoms, genetic approaches could offer to stop or reverse it. Such are the cases of choroideremia and congenital achromatopsia, currently aided with diet management (Kalatzis et al 2013;Patrício et al 2018) and eyeborg (Rochi 2009), respectively. Several genetic therapies in clinical trials have yielded promising results.…”

Section: Eye Diseasesmentioning

confidence: 99%

Curative gene therapies for rare diseases

2020

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Diseases caused by alterations in the DNA can be overcome by providing the cells or tissues with a functional copy of the mutated gene. The most common form of gene therapy implies adding an extra genetic unit into the cell. However, new genome engineering techniques also allow the modification or correction of the existing allele, providing new possibilities, especially for dominant diseases. Gene therapies have been tested for 30 years in thousands of clinical trials, but presently, we have only three authorised gene therapy products for the treatment of inherited diseases in European Union. Here, we describe the gene therapy alternatives already on the market in the European Union and expand the scope to some clinical trials. Additionally, we discuss the ethical and regulatory issues raised by the development of these new kinds of therapies. Keywords CRISPR-Cas9. Gene therapy. Genetic engineering This article is part of topical collection on Rare Diseases

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Choroideremia: molecular mechanisms and development of AAV gene therapy

Cited by 30 publications

References 100 publications

Synonymous Variant in the CHM Gene Causes Aberrant Splicing in Choroideremia

Synonymous Variant in the CHM Gene Causes Aberrant Splicing in Choroideremia

Quantification of RPE Changes in Choroideremia Using a Photoshop-Based Method

Curative gene therapies for rare diseases

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