Autofluorescence in female carriers with choroideremia: A familial case with a novel mutation in the <i>CHM</i> gene

Ortiz-Ramirez, Grecia Yael; Villanueva‐Mendoza, Cristina; Ruíz, Juan-Carlos; Reyes, Mariana; Cortés‐González, Vianney

doi:10.1080/13816810.2020.1810283

Cited by 3 publications

(2 citation statements)

References 23 publications

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“…Males are therefore severely affected by this disease, whereas female carriers present with a range of phenotype severities dependant on the extent and timing of X-chromosome inactivation. [1][2][3] As the central cone photoreceptors are generally preserved until the late stages of choroideremia, due to the centripetal nature of the degeneration, patients usually retain good visual acuity until degeneration encroaches on the fovea. [4][5][6][7] Fundus examinations of patients with choroideremia reveal characteristic centripetal retinal degeneration (Figure 1).…”

Section: Chapter 1 Introduction Backgroundmentioning

confidence: 99%

Gene therapy for choroideremia using an adeno-associated viral vector encoding Rab escort protein 1: the REGENERATE open-label trial

Cehajic-Kapetanovic,

Bellini,

Taylor

et al. 2024

Efficacy Mech Eval

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Background Choroideremia is an X-linked inherited retinal degeneration that begins in childhood with nyctalopia and loss of peripheral vision, and gradually progresses to blindness in adulthood. Choroideremia is caused by null mutations in the CHM gene, which encodes Rab escort protein 1. Objective Assessment of the efficacy and safety of a single subretinal injection of an adeno-associated virus serotype 2 vector encoding Rab escort protein 1 in patients with choroideremia. Design Multicentre open-label clinical trial of a gene therapy for choroideremia using an adeno-associated virus serotype 2-Rab escort protein 1 vector. Setting This study (NCT02407678) was conducted at two NHS eye hospitals in the UK. Participants Males aged 18 years or above, having a clinical diagnosis of choroideremia with genetic confirmation of CHM gene mutation or molecular confirmation of Rab escort protein 1 protein deficiency and having best corrected visual acuity better than or equal to 6/60 (20/200; LogMAR 1.0). Intervention Adeno-associated virus serotype 2-Rab escort protein 1 vector suspension (1 × 1012 vector particles per ml) was supplied by Nightstar Therapeutics (London, UK), now part of Biogen Inc. (Cambridge, MA, USA). Up to 0.1 ml of adeno-associated virus serotype 2-Rab escort protein 1 vector suspension, corresponding to a dose of up to 1 × 1011 vector particles, was administered to the treated eye by subretinal injection. Selection of treated eyes was randomised in participants having relatively symmetrical retinal degeneration. Main outcome measures The primary safety-related outcome was change from baseline in best corrected visual acuity in treated eyes at 24 months post treatment, with prospective efficacy evaluated by comparative change from baseline in best corrected visual acuity in treated and untreated contralateral (control) eyes. Secondary outcomes included comparative change from baseline in mean retinal sensitivity (microperimetry) and retinal anatomy (area of autofluorescence) in treated and control eyes. Visual assessments were conducted by masked assessors. Results The primary efficacy-related outcome (comparative change from baseline in best corrected visual acuity in treated and control eyes at 24 months post treatment) was not statistically different between treated eyes (−2.63 letters, standard error of the mean 2.76) and control eyes (+2.67 letters, standard error of the mean 0.768) in all 30 participants (p = 0.08). Greater loss of visual fields, possibly surgery-induced, was observed in treated eyes. Six serious adverse events were reported in the treated eyes of four participants: one surgery-related and two inflammation-related serious adverse events involving clinically significant decreases in best corrected visual acuity, and three serious adverse events in one participant involving reduction in central retinal sensitivity, but with best corrected visual acuity remaining stable. Limitations No evidence of possible efficacy of the intervention was observed, as a meaningful difference in comparative change from baseline in best corrected visual acuity in treated and control eyes was not discernible at 24 months post treatment. As choroideremia is a very slow degeneration, best corrected visual acuity in control eyes did not decline significantly during the assessment period. Conclusion Although this study has not presented evidence that reduction in visual fields caused by the intervention would be justified by the possible rescue of best corrected visual acuity, a more definitive assessment may be provided by long-term monitoring of trial participants in an observational study (NCT03584165). Trial registration This study is registered as ISRCTN15602229 (www.isrctn.com/) and NCT02407678 (https://clinicaltrials.gov/). Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 12/66/35) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 9. See the NIHR Funding and Awards website for further award information.

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Section: Chapter 1 Introduction Backgroundmentioning

confidence: 99%

Gene therapy for choroideremia using an adeno-associated viral vector encoding Rab escort protein 1: the REGENERATE open-label trial

Cehajic-Kapetanovic,

Bellini,

Taylor

et al. 2024

Efficacy Mech Eval

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“…It has been hypothesized that the degree to which female carriers are affected depends on lyonization (random X-inactivation) 12 , 16 , 26 , 27 within the RPE mosaic, which would result in patches of both mutant and normal RPE cells in which the mutant RPE cells could degenerate over the course of five or more decades of life. In particular, lyonization could explain the patchy pigmentary changes such as melanin clumping due to pigment migration or areas of RPE atrophy reported in female carriers 7 , 12 , 28 – 30 . To our knowledge, this theory has not been conclusively demonstrated to date due in part to the lack of tools for imaging the RPE at a cellular level in patients over large enough areas within the eye to detect mutant and normal patches of RPE.…”

Section: Introductionmentioning

confidence: 99%

Widespread subclinical cellular changes revealed across a neural-epithelial-vascular complex in choroideremia using adaptive optics

et al. 2022

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Choroideremia is an X-linked, blinding retinal degeneration with progressive loss of photoreceptors, retinal pigment epithelial (RPE) cells, and choriocapillaris. To study the extent to which these layers are disrupted in affected males and female carriers, we performed multimodal adaptive optics imaging to better visualize the in vivo pathogenesis of choroideremia in the living human eye. We demonstrate the presence of subclinical, widespread enlarged RPE cells present in all subjects imaged. In the fovea, the last area to be affected in choroideremia, we found greater disruption to the RPE than to either the photoreceptor or choriocapillaris layers. The unexpected finding of patches of photoreceptors that were fluorescently-labeled, but structurally and functionally normal, suggests that the RPE blood barrier function may be altered in choroideremia. Finally, we introduce a strategy for detecting enlarged cells using conventional ophthalmic imaging instrumentation. These findings establish that there is subclinical polymegathism of RPE cells in choroideremia.

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Choroideremia: Toward Regulatory Approval of Retinal Gene Therapy

Yusuf

MacLaren

2023

Cold Spring Harb Perspect Med

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Autofluorescence in female carriers with choroideremia: A familial case with a novel mutation in the CHM gene

Cited by 3 publications

References 23 publications

Gene therapy for choroideremia using an adeno-associated viral vector encoding Rab escort protein 1: the REGENERATE open-label trial

Gene therapy for choroideremia using an adeno-associated viral vector encoding Rab escort protein 1: the REGENERATE open-label trial

Widespread subclinical cellular changes revealed across a neural-epithelial-vascular complex in choroideremia using adaptive optics

Choroideremia: Toward Regulatory Approval of Retinal Gene Therapy

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