Abstract
Background and objectives: Choroideremia (CHM) is an X-linked recessive chorioretinal dystrophy caused by mutations involving the CHM gene. Gene therapy has entered late-phase clinical trials, although there have been variable results. This review gives a summary on the outcomes of phase I/II CHM gene therapy trials and describes other potential experimental therapies. Materials and Methods: A Medline (National Library of Medicine, Bethesda, MD, USA) search was performed to identify all articles describing gene therapy treatments available for CHM. Results: Five phase I/II clinical trials that reported subretinal injection of adeno-associated virus Rab escort protein 1 (AAV2.REP1) vector in CHM patients were included. The Oxford study (NCT01461213) included 14 patients; a median gain of 5.5 ± 6.8 SD (−6 min, 18 max) early treatment diabetic retinopathy study (ETDRS) letters was reported. The Tubingen study (NCT02671539) included six patients; only one patient had an improvement of 17 ETDRS letters. The Alberta study (NCT02077361) enrolled six patients, and it reported a minimal vision change, except for one patient who gained 15 ETDRS letters. Six patients were enrolled in the Miami trial (NCT02553135), which reported a median gain of 2 ± 4 SD (−1 min, 10 max) ETDRS letters. The Philadelphia study (NCT02341807) included 10 patients; best corrected visual acuity (BCVA) returned to baseline in all by one-year follow-up, but one patient had −17 ETDRS letters from baseline. Overall, 40 patients were enrolled in trials, and 34 had 2 years of follow-up, with a median gain of 1.5 ± 7.2 SD (−14 min, 18 max) in ETDRS letters. Conclusions: The primary endpoint, BCVA following gene therapy in CHM, showed a marginal improvement with variability between trials. Optimizing surgical technique and pre-, peri-, and post-operative management with immunosuppressants to minimize any adverse ocular inflammatory events could lead to reduced incidence of complications. The ideal therapeutic window needs to be addressed to ensure that the necessary cell types are adequately transduced, minimizing viral toxicity, to prolong long-term transgenic potential. Long-term efficacy will be addressed by ongoing studies.
Highlights
IntroductionChoroideremia (CHM) (MIM #303100) is a rare X-linked recessive disorder resulting in progressive degeneration of the photoreceptors, retinal pigment epithelium (RPE), and choroid [1,2]
Five CHM gene therapy phase I/II clinical trials were identified for inclusion in this review, and Table 2 summarizes data items from each one [42,43,44,45,46]
14 patients were recruited at different disease stages and underwent pars plana vitrectomy followed by retinotomy and injection of AAV2.Rab escort protein 1 (REP1) particles; the median age was 45.5 ± 12.6 SD years (24 min, 72 max)
Summary
Choroideremia (CHM) (MIM #303100) is a rare X-linked recessive disorder resulting in progressive degeneration of the photoreceptors, retinal pigment epithelium (RPE), and choroid [1,2]. It has a prevalence of 1 in 50,000–100,000 and is caused by mutations in the CHM gene on chromosome Xq21.2 [3]. Six patients were enrolled in the Miami trial (NCT02553135), which reported a median gain of 2 ± 4 SD (−1 min, 10 max) ETDRS letters. 40 patients were enrolled in trials, and had 2 years of follow-up, with a median gain of 1.5 ± 7.2 SD (−14 min, 18 max) in ETDRS letters
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