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. 2018;13(3):129-138.
doi: 10.1080/17469899.2018.1475232. Epub 2018 May 18.

Ocular gene therapy for choroideremia: clinical trials and future perspectives

Kanmin Xue  1 , Robert E MacLaren  1
Affiliations

Ocular gene therapy for choroideremia: clinical trials and future perspectives

Kanmin Xue et al. Expert Rev Ophthalmol. 2018.

Abstract

Introduction: Gene therapy offers the potential for targeted replacement of single gene defects in inherited retinal degenerations.

Areas covered: Choroideremia is an X-linked blinding retinal disease resulting from deficiency of the CHM gene product, REP1. The disease represents an ideal target for retinal gene therapy, as it is readily diagnosed in the clinic, relatively homogenous in phenotype and slow progressing, thereby providing a wide therapeutic window for intervention. Ongoing clinical trials of retinal gene therapy for choroideremia using an adeno-associated viral vector have demonstrated safety and early efficacy. We review the clinical characteristics of the disease with a view to interpreting the findings of gene therapy clinical trials and discuss future directions.

Expert commentary: Choroideremia gene therapy has so far demonstrated good safety profile and early functional visual acuity gains in a proportion of trial participants, which appear to be sustained.

Keywords: AAV; CHM; REP1; adeno-associated virus; choroideremia; gene therapy.

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Conflict of interest statement

Declaration of interest RE MacLaren is the scientific founder of Nightstar Therapeutics Inc. RE MacLaren is a consultant to Spark Therapeutics Inc. Neither companies had any role in the writing of this review article. The views expressed are those of the authors and not necessarily those of the Wellcome Trust, the National Health Service, the NIHR, or the UK Department of Health. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. One peer reviewer was a scientific director of a trial being run by Spark Therapeutics.

Figures

Figure 1
Figure 1
Multimodal retinal imaging in choroideremia. (A) Infra-red confocal scanning laser ophthalmoscopy (cSLO). (B) Blue-light (488 nm) fundus autofluorescence showing an island of preserved RPE. (C) Spectrial domain optical coherence tomography (SD-OCT). (D) En-face OCT. (E) Near infra-red (805 nm) autofluorescence (NIR-AF) indicating an area of preserved melanin pigment. (F) Fluorescein angiography. (G) Indocyanin green angiography. (H) Angio-OCT with color coded density map of choroidal vasculature underlying the residual retinal island. Full color available online.
Figure 2
Figure 2
Gradual reduction in autofluorescence area over 6 years in an eye with choroideremia (A-G). (H) Schematic line drawing illustrating the outline of the island of residual autofluorescence in this eye in relation to the fovea (cross) and optic nerve head.
Figure 3
Figure 3
Schematic for the absorption of a subretinal bleb following imaginary injection of vector marked by the black line. Concentric rings illustrate the predicted shrinkage of a hypothetical circular subretinal bleb at set time intervals based on Fick’s law of diffusion and surface area of a hemisphere. Due to the concave shape of the eye, the subretinal fluid will be deeper centrally and this will be the last point from which fluid will be reabsorbed as the retina reattaches. Hence, excluding any slight effects of gravity, retinal pigment epithelial cells lying in the central part of the bleb (white to red) are likely to have far more exposure time in contact with the vector solution than cells located in the periphery (blue to green). This is likely to result in a dose-profile gradient along the radial axis. Full color available online.
See this image and copyright information in PMC

References

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