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Ian M MacDonald, Ioannis Dimopoulos, Stephanie Chan, Matthew Tennant, Riz Somani; Ocular Gene Therapy for Choroideremia: the Alberta Experience. Invest. Ophthalmol. Vis. Sci. 201657(12):.
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To undertake a 2-year, non-randomized (open label), Phase 1/2 efficacy and safety gene therapy trial for choroideremia (CHM) using an adeno-associated viral vector (AAV2) encoding Rab-escort protein 1 (REP1) in 6 subjects affected by CHM. One eye of each subject will be injected, with the fellow eye used as a comparator. The primary outcome measure will be change in best-corrected visual acuity (BCVA) measured in Early Treatment Diabetic Retinopathy Study (ETDRS) letters in the treated eye compared to the untreated eye. Additional anatomical (change in autofluorescence area) and functional (change in microperimetry sensitivity) outcome measures will be compared between treated and untreated eyes to determine efficacy.
Twenty candidates with CHM, genotyped for mutations in the CHM gene, or lacking REP1, the gene product, were considered to be eligible if they met the following inclusion criteria: 1) BCVA equal to or worse than 20/30 but better than or equal to 20/200 in the study eye, 2) active degeneration of the retina with spectral domain optical coherence tomography (SD-OCT) changes visible within the central macula, and 3) the expectation of significant decline in visual function without any intervention over the subsequent 5 years. Key exclusion criteria were asymmetrical retinal disease or other ocular morbidity which might confound adopting the fellow eye as a long-term comparator. Six candidates (age: 31-43 years old) met the inclusion criteria and received a single sub-retinal injection of 0.1ml of AAV2.REP1, containing 1011 genome particles after foveal detachment with balaced salt solution (BSS).
At baseline, mean BCVA was 65.17 ETDRS letters. In all cases, and as expected post-foveal detachment, the treated subject lost central visual acuity after the injection (average BCVA=35.83) . SD-OCT imaging showed resolution of the subretinal fluid pocket within 1-7 days. By three months, all subjects had regained their baseline visual acuity and will continue to be monitored over a 2-year period.
In this limited sample, AAV2.REP1 gene replacement in CHM patients appears to be safe. Subjects continue to be monitored to determine which outcome measures may predict efficacy and inform the development of larger planned studies.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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