PurposeReports of gene therapy-associated retinal atrophies and inflammation have highlighted the importance of preclinical safety assessments of adeno-associated virus (AAV) vector systems. We evaluated in nonhuman primates (NHPs) the ocular safety and toxicology of a novel AAV gene therapy targeting retinitis pigmentosa caused by mutations in PDE6A, which has since been used in a phase I/II clinical trial (NCT04611503).MethodsA total of 34 healthy cynomolgus animals (Macaca fascicularis) were treated with subretinal injections of rAAV.hPDE6A and followed over 13 weeks. Three dose levels (low: 1 × 1011, intermediate: 5 × 1011, and high: 1 × 1012 vector genomes [vg]) were compared to sham-injected controls. Safety and toxicity were determined using ophthalmic examinations, electroretinography, ocular histology, and retinal imaging.ResultsAt the low and intermediate doses, inflammation was mild, electroretinography response was unimpeded, and histology results were in line with surgically induced changes. In contrast, three high-dose animals displayed atrophic changes of the retina and abnormalities in electroretinography, which were considered test article related and adverse.ConclusionsA single subretinal injection of up to 5 × 1011 vg was well tolerated, and a 10-fold lower dose of 5 × 1010 vg was chosen as the starting dose for the ongoing phase I/II clinical trial. Atrophic retinal changes and abnormalities in electroretinography emerged as dose-limiting findings in the high-dose cohort.Translational RelevanceThis study demonstrates that treatment candidate rAAV.PDE6A was well tolerated in NHPs. Occurrence of retinal atrophy as a dose-limiting finding highlights the importance of further study into the mechanisms of atrophy induction after retinal gene therapy.
