Retinal gene therapy in patients with choroideremia: Initial fi ndings from a phase 1/2 clinical trial

Background Choroideremia 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 eff ects of retinal gene therapy with an adenoassociated viral (AAV) vector encoding REP1 (AAV.REP1) in patients with this disease. Methods In 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. Findings Despite 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 mm-rfsti of surviving retina (r=0.82, p=0.04). By contrast, small non-signifi cant reductions (p