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Nitza Thomasson, Anne Galy, Serge Fitoussi, Sandrine Meunier, Scott Uretsky, Jean-Philippe Combal; Relevance of NHP safety studies for ocular delivery of AAV-based gene therapy in humans: Example of GS010 (rAAV2/2-ND4) local tolerability, shedding and immunogenicity for the treatment of Leber Hereditary Optic Neuropathy (LHON), after intravitreal (IVT) injection in non-human primates (NHP) and in LHON patients.. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):1087. doi: https://doi.org/.
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GS010 for treatment of LHON has entered the clinical phase with recent first-in-man safety study (Clinicaltrial.gov # NCT02064569). Preclinical development of GS010 involved assessment of local tolerability, shedding and immunogenicity after IVT injection in Cynomolgus monkey to determine safety of human administration. We present data obtained in the NHP studies and preliminary, accumulating safety data from the first-in-man safety trial of gene therapy in LHON patients with the ND4 mutation.
Local tolerability was assessed using slit lamp biomicroscopy, fundus photography and IOP measurements. Shedding was evaluated at different time points (up to 1 month in blood and urine and at 3 months in tears for the NHP study; up to 2 weeks post IVT administration in blood, urine, and tears human samples) using qPCR analysis. Immunogenicity was assessed by quantifying AAV2 neutralizing antibodies (Nab; with a luciferase assay) in the serum before and after IVT GS010 injection.
Injection of NHP eye with GS010 at 4.3E10vg/eye (human corresponding dose 9E10vg/eye) induced mild to moderate anterior uveitis in 3/18 eyes. Mild intermediate uveitis was observed in 1/18 eye at the dose of 3E11 vg/eye (human corresponding dose 6.6E11vg/eye). In patients, 2/9 eyes experienced mild anterior chamber inflammation at a dose of 3E10vg/eye and 1/9 at a dose of 9E10vg/eye. One eye out of 9 experienced mild vitreous inflammation at a dose of 9E10vg/eye.<br /> Shedding of vector DNA in monkey was observed in blood up to 28 days and in urine up to 8days but was not detected in tears at three months. In patients, no vector DNA copies were detected in urine samples and in blood only 1/9 patients was positive only at 24h post IVT injection. All tears samples were positive for vector DNA up to 6h post IVT administration. Nab levels in serum showed an increase from day 15 post IVT administration in monkey and in human.
NHP study predicted safety outcomes well; especially ocular inflammation, shedding, and immunogenicity were similar in NHP and patients. NHPs are a relevant species for testing AAV mediated ocular gene therapies intended for humans.
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