Choroideremia Gene Therapy Phase 2 Clinical Trial: 24-Month Results.
Lam BL., Davis JL., Gregori NZ., MacLaren RE., Girach A., Verriotto JD., Rodriguez B., Rosa PR., Zhang X., Feuer WJ.
PURPOSE: To report the final results of a phase 2 high-dose gene therapy clinical trial in choroideremia. METHODS: DESIGN: Phase 2 clinical trial. PARTICIPANTS: Six men (age 32-72 years) with genetically-confirmed advanced choroideremia. Patients received subfoveal injection of AAV2-REP1 (1011 genome particles in 0.1 mL) in the worse-sighted eye. OUTCOME MEASURES: Primary measure was best-corrected visual acuity (BCVA) change from baseline in the treated eye compared to the untreated eye. Secondary endpoints included change from baseline in microperimetry, fundus autofluorescence, and spectral-domain optical coherence tomography (OCT). Safety evaluations included adverse events, viral shedding in body fluids, and vector antibody responses. RESULTS: Baseline mean ETDRS BCVA was 65.3±8.8 (SD, range 56-77, 20/32-20/80) letters in the treated eyes and 77.0±4.2 (69-81, 20/25-20/40) letters in the untreated eyes. At two years, one treated eye improved by 10 letters and another by 5 letters, while one untreated eye improved by 4 letters. All other eyes were within 2 letters of baseline. Baseline microperimetry sensitivities in the treated eyes were poor (1.2±2.1 (0,5.1) dB) and showed no significant change. No serious adverse event occurred. Two patients developed an atrophic retinal hole in a non-functioning macular area where baseline OCT showed pre-existing thinning. Intraoperative microscope-integrated OCT allowed proper subretinal injection with avoidance of excessive foveal stretching and macular hole formation. CONCLUSIONS: Sustained improvement or maintenance of BCVA is achievable in choroideremia with high-dose AAV2-REP1 indicating BCVA is a viable primary outcome in advanced choroideremia. Choroideremia gene therapy delivered with intraoperative OCT has a good safety profile.