Nonclinical Safety Evaluation of scAAV8- for Treatment of Retinitis Pigmentosa.

Retinitis pigmentosa is a form of retinal degeneration usually caused by genetic mutations affecting key functional proteins. We have previously demonstrated efficacy in a mouse model of deficiency with a self-complementary AAV8 vector carrying the gene for human under control of a short promoter (CPK850). In this article, we describe the nonclinical safety profile of this construct as well as updated efficacy data in the intended clinical formulation. In mice dosed at a range of CPK850 levels, a minimum efficacious dose of 3 × 10 vg in a volume of 1 μL was observed. For safety assessment in these and mice, optical coherence tomography (OCT) and histopathological analysis indicated retinal thinning that appeared to be dose-dependent for both genotypes, with no qualitative difference noted between and mice. In a non-human primate study, mRNA expression was detected and dose dependent intraocular inflammation and retinal thinning were observed. Inflammation resolved slowly over time and did not appear to be exacerbated in the presence of anti-AAV8 antibodies. Biodistribution was evaluated in rats and satellite animals in the non-human primate study. The vector was largely detected in ocular tissues and low levels in the optic nerve, superior colliculus, and lateral geniculate nucleus, with limited distribution outside of these tissues. These data suggest that an initial subretinal dose of ∼3 × 10 vg/μL CPK850 can safely be used in clinical trials.