Optimisation of RPE65 gene delivery for treatment of Leber congenital amaurosis patients

Summary Virally‐mediated gene therapy to treat inherited retinal disorders has proven to be safe and well tolerated through a number of phase I/II clinical trials. RPE65 deficiency is the cause of Leber congenital amaurosis type 2 and clinical trials, including our own, using recombinant AAV serotype 2 to deliver the human RPE65 gene into the patients’ RPE cells have shown moderate levels of efficacy. We aim to increase the potency and persistence of treatment effect by employing a range of optimisations to the recombinant AAV gene therapy vector. We assessed the preclinical efficacy of a novel gene therapy vector for RPE65 gene replacement in vitro and in vivo following optimisation of the viral serotype, transgene promoter and transgene sequence. We observed a 300‐fold increase in efficacy in a mouse model lacking Rpe65 when compared to the original AAV2 gene therapy vector. We aim to bring this vector forward for a new phase I/II clinical trial in patients with LCA2.