267. Phase I Gene Therapy Preliminary Clinical Results for Treatment of ND4 Leber Hereditary Optic Neuropathy with rAAV2-2-ND4

Introduction Leber Hereditary Optic Neuropathy (LHON) is a rare mitochondrial genetic disorder predominantly affecting young males. Affected patients experience bilateral severe central vision loss. Currently no therapy is approved in the United States to prevent, halt or reverse vision loss due to LHON. Preliminary safety and pharmacodynamic results of a first-in-man trial of GS010, a gene therapy candidate for patients with LHON carrying the ND4 mutation will be presented. Methods GS010 is a recombinant adeno-associated viral vector, serotype 2, carrying the wild-type ND4 gene (rAAV2/2-ND4) and is an experimental gene therapy for the treatment of LHON due to the G11778A ND4 mitochondrial mutation. GS010 has received orphan drug designation in EU & USA. GS010 contains a Mitochondrial Targeting Sequence (MTS) that allows localization of the wild-type protein to the mitochondrion, enabling restoration of mitochondrial function. An open-label Phase I/IIa safety study (NCT02064569) included patients with vision loss due to ND4 LHON and has completed recruitment. Four dose escalation cohorts and an extension cohort were comprised of 3 patients each. Patients received a single intra-vitreal injection of rAAV2/2-ND4 in their worse seeing eye. Primary outcome was the occurrence of adverse events (AE). Secondary outcomes included immune response to AAV2 and evaluation of visual function. Results Systemic safety was excellent as no unexpected adverse events occurred. Ocular tolerability was good with mostly mild inflammation that were responsive to and resolve with standard therapies. Of the first 9 patients with 48 week follow up, preliminary results indicate that symptom duration could impact magnitude of treatment effect. Additionally, baseline vision status at time of treatment also indicate a relation with potential greater magnitude of effect which was noted with relatively shorter disease duration (< 2 years). These data confirm the importance of treating early from onset of vision loss. The RESCUE (NCT02652767) and REVERSE (NCT02652780) Phase III studies of GS010 have been initiated in the United States and some European Union countries. Both studies are randomized, double-masked, sham-controlled trials and will specifically include patients up to 6 months and one year after the onset of vision loss.