Characterizing the Natural History of Visual Function in Choroideremia Using Microperimetry and Multimodal Retinal Imaging

Jolly, Jasleen K; Xue, Kanmin; Edwards, Thomas L.; Groppe, Markus; MacLaren, Robert E.

doi:10.1167/iovs.17-22486

Cited by 84 publications

(98 citation statements)

References 28 publications

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“…The optical coherence tomography (OCT) image may appear normal or show slight thinning of the outer nuclear layer corresponding to shortening of photoreceptor cell outer segments (58). Progressive constriction of visual fields over time, due to the degeneration of retinal cells impinging onto the fovea, leads to vision loss in early adulthood (59). This may be visualized on fundus photography and OCT as preserved, scallop-edged islands of pigmentation (Fig.…”

Section: Inherited Retinal Diseasesmentioning

confidence: 99%

“…1b) surrounded by choroidal atrophy (58). Microperimetry testing at this point may reveal a less stable fixation area (59). A mean onset of moderate visual impairment occurs in the fifth decade (Lam BL, et al .…”

Section: Inherited Retinal Diseasesmentioning

confidence: 99%

“…2018). However, best-corrected visual acuity (BCVA) especially can vary widely among patients depending on whether the fovea has been affected by retinal atrophy and how much of the fovea is preserved on a residual island (59). In late-stage choroideremia, a small island of residual RPE may be seen (Fig.…”

Section: Inherited Retinal Diseasesmentioning

confidence: 99%

“…Although total blindness is likely in patients with end-stage disease owing to total retinal atrophy (after approximately the sixth decade of life) (54,57,58), preserved photoreceptor cells, even with aberrant outer segments, may provide a small amount of visual acuity, albeit with a very limited visual field (58). While anatomical endpoints remain symmetrical, during mid- to late-stage disease, visual acuity and mean macular threshold sensitivity may become asymmetric between eyes (59). Similarly, the nasal and temporal areas of the central macula have been found to decline asymmetrically, with the area nasal to the fovea degenerating at a faster rate than temporal (59).…”

Section: Inherited Retinal Diseasesmentioning

confidence: 99%

“…While anatomical endpoints remain symmetrical, during mid- to late-stage disease, visual acuity and mean macular threshold sensitivity may become asymmetric between eyes (59). Similarly, the nasal and temporal areas of the central macula have been found to decline asymmetrically, with the area nasal to the fovea degenerating at a faster rate than temporal (59). …”

Section: Inherited Retinal Diseasesmentioning

confidence: 99%

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Adeno-Associated Viral Gene Therapy for Inherited Retinal Disease

et al. 2019

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Inherited retinal diseases (IRDs) are a group of rare, heterogenous eye disorders caused by gene mutations that result in degeneration of the retina. There are currently limited treatment options for IRDs; however, retinal gene therapy holds great promise for the treatment of different forms of inherited blindness. One such IRD for which gene therapy has shown positive initial results is choroideremia, a rare, X-linked degenerative disorder of the retina and choroid. Mutation of the CHM gene leads to an absence of functional Rab escort protein 1 (REP1), which causes retinal pigment epithelium cell death and photoreceptor degeneration. The condition presents in childhood as night blindness, followed by progressive constriction of visual fields, generally leading to vision loss in early adulthood and total blindness thereafter. A recently developed adeno-associated virus-2 (AAV2) vector construct encoding REP1 (AAV2-REP1) has been shown to deliver a functional version of the CHM gene into the retinal pigment epithelium and photoreceptor cells. Phase 1 and 2 studies of AAV2-REP1 in patients with choroideremia have produced encouraging results, suggesting that it is possible not only to slow or stop the decline in vision following treatment with AAV2-REP1, but also to improve visual acuity in some patients.

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Section: Inherited Retinal Diseasesmentioning

confidence: 99%

Section: Inherited Retinal Diseasesmentioning

confidence: 99%

Section: Inherited Retinal Diseasesmentioning

confidence: 99%

Section: Inherited Retinal Diseasesmentioning

confidence: 99%

Section: Inherited Retinal Diseasesmentioning

confidence: 99%

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Adeno-Associated Viral Gene Therapy for Inherited Retinal Disease

et al. 2019

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Association of Messenger RNA Level With Phenotype in Patients With Choroideremia

et al. 2020

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IMPORTANCE Gene therapy is a promising treatment for choroideremia, an X-linked retinal degeneration. The required minimum level of gene expression to ameliorate degeneration rate is unknown. This can be interrogated by exploring the association between messenger RNA (mRNA) levels and phenotype in mildly affected patients with choroideremia.OBJECTIVE To analyze CHM mRNA splicing outcomes in 2 unrelated patients with the same c.940+3delA CHM splice site variant identified as mildly affected from a previous study of patients with choroideremia. DESIGN, SETTING, AND PARTICIPANTSIn this retrospective observational case series, 2 patients with c.940+3delA CHM variants treated at a single tertiary referral center were studied. In addition, a third patient with a c.940+2T>A variant that disrupts the canonical dinucleotide sequence at the same donor site served as a positive control. Data were collected from October 2013 to July 2018. MAIN OUTCOMES AND MEASURESCentral area of residual fundus autofluorescence was used as a biomarker for disease progression. CHM transcript splicing was assessed by both end point and quantitative polymerase chain reaction. Rab escort protein 1 (REP1) expression was assessed by immunoblot. RESULTSThe 2 mildly affected patients with c.940+3delA variants had large areas of residual autofluorescence for their age and longer degeneration half-lives compared with the previous cohort of patients with choroideremia. The control patient with a c.940+2T>A variant had a residual autofluorescence area within the range expected for his age. Both patients with the c.940+3delA variant expressed residual levels of full-length CHM mRNA transcripts relative to the predominant truncated transcript (mean [SEM] residual level: patient 1, 2.3% [0.3]; patient 2, 4.7% [0.2]), equivalent to approximately less than 1% of the level of full-length CHM expressed in nonaffected individuals. Full-length CHM expression was undetectable in the control patient. REP1 expression was less than the threshold for detection both in patients 1 and 2 and the control patient compared with wild-type controls. CONCLUSIONS AND RELEVANCEThese results demonstrate the first genotype-phenotype association in choroideremia. A +3 deletion in intron 7 is sufficient to cause choroideremia in a milder form. If replicated with gene therapy, these findings would suggest that relatively low expression (less than 1%) of the wild-type levels of mRNA would be sufficient to slow disease progression.

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