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Jose Alain Sahel, Scott Uretsky, Jean Philppe Combal, Anne Galy, Nitza Thomasson, Serge Fitoussi, Marisol Corral-Debrinsky, Geraldine Honnet, Catherine Vignal; Preliminary safety and tolerability results of intravitreal administration of GS010, a recombinant adeno-associated viral vector serotype 2 (rAAV2/2) containing human wildtype mitochondrial NADH dehydrogenase 4 (ND4) gene in patients with Leber Hereditary Optic Neuropathy (LHON) due to the G11778A ND4 mitochondrial DNA mutation. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):1088.
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Currently there is no effective therapy for LHON. Our aim is to report the results of a first-in-man safety trial of an experimental gene therapy, GS010, in patients with LHON. An open-label, dose escalation, prospective clinical trial is ongoing (NCT02064569).
Three cohorts each comprised of 3 patients with the ND4 mutation and severe visual loss (≤20/200) received ascending doses of intravitreal (IVT) GS010. Baseline general and ophthalmic examinations, laboratory and EKG parameters were obtained. Paracentesis and intra-ocular pressure (IOP) lowering treatment preceded IVT. In-patient observation for 24-hours post-IVT ensued with IOP check at 0.5, 1, 2, 4, and 24-hours. Follow-up visits including vital signs, IOP, ophthalmic examinations, laboratory evaluation, immune-monitoring and assessment of adverse events (AE, SAE) were conducted at 0.5, 1, 2, 4, 8, 12, 24, 36 and 48-weeks post-IVT. Bio-dissemination in blood, urine and tears were evaluated for two weeks post-IVT. The first, second and third cohorts received 9E+09vg/eye, 3E+10vg/eye and 9E+10vg/eye respectively. A data safety monitoring board (DSMB) evaluated the safety of each cohort prior to dose escalation.
12 LHON patients were screened, 9 were included (time since onset 4.33-492 months). No SAE or treatment-related systemic AE occurred. 6/9 patients had non-sustained, topical-treatment responsive, elevated IOP; 4/6 patients within 4-hours post-IVT and 2/6 at 2-weeks post-IVT [elevated IOP range: 23-34mmHg]. 4/9 patients experienced mild, treatment responsive anterior chamber inflammation (ACI); 2/9 mild vitreous inflammation. No IVT-GS010 related or other event of visual acuity decline occurred.
Overall safety and tolerability of a single IVT injection of GS010 was good in all cohorts. Post-IVT IOP elevation (mechanistic) and mild ocular inflammation (pre-clinical studies) occurred as expected; both were mild and reversible (ACI) with local treatment. These results allow for dose escalation necessary to identify the highest tolerated or maximal dose of GS010 that will be used in upcoming studies of clinical efficacy of GS010 in LHON G11778A patients.
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