Treatment of Leber Congenital Amaurosis (LCA) caused by RPE65 gene mutations with recombinant adeno-associated virus (rAAV) mediated subretinal gene replacement therapy has been shown to be safe and effective through phase I/II clinical trials. The purpose of the four studies that comprise this thesis were to further evaluate gene therapy outcomes using the RPE65-deficient canine model. To study the success of treatment in the presence of retinal degeneration treatment of older RPE65-deficient dogs (2-6 years of age) was performed, demonstrating improved retinal function, as assessed by electroretinography (ERG), and improved vision testing outcomes. The effect of immune responses on treatment the second eye after prior treatment of the first eye of RPE65-deficient dogs was also studied, finding evidence of safety and efficacy equal to that seen in the first treated eye. These findings supported inclusion of the second eye in current human clinical trials, and this has since commenced. For these and subsequent studies a description of the phenotype of older RPE65-deficient dogs, and changes with age were evaluated, this included description of a previously unreported region of photoreceptor loss at the area centralis. Additionally, these studies required evidence that improvements in vision testing outcomes of an objective canine vision testing apparatus were due to the given therapy alone, and this was provided.
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