Gene therapy clinical trials for childhood blindness and its applications for ocular, auditory and renal ciliopathies

Abstract

Methods In Phase I/II clinical trials, 12 subjects with confirmed mutations in the RPE65 gene causing inherited retinal degeneration were given a unilateral sub-retinal injection of AAV.RPE65 into the worse seeing-eye. Objective and subjective visual testing were performed at baseline and following intervention. Subsequently, 11/12 subjects received injections in the contralateral eye, in a Phase II follow on study. These results have initiated the first Phase III clinical trial for retinal disease. The methods and technology used in this study have enabled gene transfer to cells involved with ciliopathies. Unilateral subretinal, intraotocyst, and retrograde ureteral injections of AAV vectors were carried out in cohorts of mice. Intra-otocyst injections were carried out at embryonic day 12; ocular and renal injections were performed in adult mice. The transgene cassette consisted of a CMV-promoted EGFP and/or a luciferase transgene. Transgene expression was evaluated qualitatively and quantitatively over time. Cellular specificity of expression was evaluated histologically. Delivery of the vector was well tolerated locally and systemically and the animals showed no alteration in behavior or general well-being.