Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial

Abstract

SummaryBackgroundChoroideremia is an X-linked recessive disease that leads to blindness due to mutations in the CHM gene, which encodes the Rab escort protein 1 (REP1). We assessed the effects of retinal gene therapy with an adeno-associated viral (AAV) vector encoding REP1 (AAV.REP1) in patients with this disease.MethodsIn a multicentre clinical trial, six male patients (aged 35–63 years) with choroideremia were administered AAV.REP1 (0·6–1·0×1010 genome particles, subfoveal injection). Visual function tests included best corrected visual acuity, microperimetry, and retinal sensitivity tests for comparison of baseline values with 6 months after surgery. This study is registered with ClinicalTrials.gov, number NCT01461213.FindingsDespite undergoing retinal detachment, which normally reduces vision, two patients with advanced choroideremia who had low baseline best corrected visual acuity gained 21 letters and 11 letters (more than two and four lines of vision). Four other patients with near normal best corrected visual acuity at baseline recovered to within one to three letters. Mean gain in visual acuity overall was 3·8 letters (SE 4·1). Maximal sensitivity measured with dark-adapted microperimetry increased in the treated eyes from 23·0 dB (SE 1·1) at baseline to 25·3 dB (1·3) after treatment (increase 2·3 dB [95% CI 0·8–3·8]). In all patients, over the 6 months, the increase in retinal sensitivity in the treated eyes (mean 1·7 [SE 1·0]) was correlated with the vector dose administered per mm2 of surviving retina (r=0·82, p=0·04). By contrast, small non-significant reductions (p>0·05) were noted in the control eyes in both maximal sensitivity (–0·8 dB [1·5]) and mean sensitivity (–1·6 dB [0·9]). One patient in whom the vector was not administered to the fovea re-established variable eccentric fixation that included the ectopic island of surviving retinal pigment epithelium that had been exposed to vector.InterpretationThe initial results of this retinal gene therapy trial are consistent with improved rod and cone function that overcome any negative effects of retinal detachment. These findings lend support to further assessment of gene therapy in the treatment of choroideremia and other diseases, such as age-related macular degeneration, for which intervention should ideally be applied before the onset of retinal thinning.FundingUK Department of Health and Wellcome Trust.

A New Promoter Allows Optogenetic Vision Restoration with Enhanced Sensitivity in Macaque Retina

“…25 Therefore, we chose AAV2 for its known safety and efficacy in targeting RGCs in NHP studies [27][28][29] and the large body of work using this vector in human clinical trials. [20][21][22][23]44 High-level expression with a limited viral dose being a major parameter in obtaining functional expression, we designed a new RGC-specific promoter, driving strong transgene expression in RGCs. We show that this promoter, named SNCG, drives expression in twice as many RGCs compared to the ubiquitous CMV promoter.…”

“…First, optogenetically equipped cells require very high-level opsin expression, as there is no amplification cascade behind microbial opsins. 19 Although adeno-associated viruses (AAVs) have a favorable safety profile in clinical gene therapy, [20][21][22][23] their safety is dose dependent, 24,25 limiting the injected dose. This makes our ability to obtain functional-level microbial opsin expression with a safe viral dose uncertain.…”

“…AAV2 was chosen for gene delivery due to its efficacy in targeting RGCs and to the large body of knowledge using this serotype in non-human primate (NHP) studies 24,28,29 and in human clinical trials. [20][21][22][23]30 To obtain functional responses at lower light intensities, we optimized several parameters. First, we used a human codon-optimized Ca 2+ -permeable channelrhodopsin (CatCh), shown to be 70 times more sensitive than channelrhodopsin.…”

Comprehensive genotyping reveals RPE65 as the most frequently mutated gene in Leber congenital amaurosis in Denmark

“…The RPE65 and CHM gene augmentation trials in patients with LCA [7][8][9] and choroideremia, 10 respectively, have been milestones in the retinal therapeutics field. An oral retinoid-based treatment was also reported to be beneficial for individuals with RPE65 or LRAT mutations.…”

Curing blindness: Vision quest

“…Most researchers agree that the best approach is to replace the faulty gene when patients are young, before the degeneration starts or at least when there are more viable cells to save. That could mean doing retinal surgery in someone with good vision -a difficult decision, says Robert MacLaren, an ophthalmologist at the University of Oxford, UK, who is running a gene-therapy clinical trial for another form of congenital blindness 7 . "That is where the risks are greatest, but so are the gains. "…”