Intravitreal rAAV2/2-ND4 (GS010): A gene therapy for vision loss in Leber’s Hereditary Optic Neuropathy (LHON) caused by the G11778A ND4 mitochondrial mutation (S26.005)

Objective: To assess the safety of a single intravitreal injection (IVI) of rAAV2/2- ND4 (GS010), an investigational gene therapy for vision loss due to ND4 LHON. Background: LHON causes severe bilateral central vision loss. rAAV2/2- ND4 is a gene therapy utilizing allotopic expression to deliver wildtype ND4 protein to mitochondria. Design/Methods: A Phase I/IIa (NCT02064569) dose-escalation safety study enrolled ND4 LHON subjects, who received a single IVI of rAAV2/2- ND4 in their worst-seeing eye. Occurrence of adverse events (AE) was the primary objective; secondary objectives included immune response to AAV and evaluation of visual function. Results: Fifteen patients were enrolled. No systemic side effects or SAE were related to study drug or procedures. Common ocular side effects included inflammation, intraocular pressure (IOP) elevation and keratopathy. Ocular inflammation, expected based on pre-clinical studies, included anterior chamber or vitreous inflammation, was mostly mild and treatment responsive with resolution. IOP elevation occurred the day of treatment, associated with injection volume (180 μL), or later associated with ocular inflammation. IOP elevations were mild, non-sustained and responded to topical therapies. Keratopathy was treated with ocular lubrication. No visual or ocular sequelae were reported as a consequence of these side effects. Baseline and post-treatment immune status to AAV was variable; no consistent correlation was noted with the occurrence or severity of ocular inflammation. The difference between treated and untreated eyes in mean change from baseline to week 48 revealed that patients with more recent onset of vision loss and better baseline acuity had a 0.338 LogMAR improvement favoring the treated eye. This improvement was not seen in more chronically and worse affected patients. Conclusions: rAAV2/2- ND4 was well tolerated. Ocular side effects were mostly mild and treatment responsive with resolution. Preliminary data indicates a potential treatment effect in more recently affected patients, supporting the protocol strategy of ongoing Phase III trials (NCT02652767, NCT02652780). Disclosure: Dr. Uretsky has received personal compensation for activities with GenSight Biologics as an employee. Dr. Uretsky holds stock and/or stock options in GenSight Biologics. Dr. Vignal-Clermont has received personal compensation for activities with GenSight Biologics as a consultant. Dr. Thomasson has received personal compensation for activities with GenSight Biologics. Dr. Bouquet has received personal compensation for activities with GenSight Biologics as an employee. GenSight Biologics,,,,,, Dr. Combal has received personal compensation for activities with GenSight Biologics as an employee. Dr. Fitoussi has received personal compensation for activities with GenSight Biologics as an employee. Dr. Sahel has received personal compensation for activities. Dr. Sahel holds stock and/or stock options in Gensight.