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Nitza Thomasson, Hélène Cwerman-Thibault, Sébastien Augustin, Manuel Simonuti, José-Alain Sahel, Didier Pruneau, Marie Montus, Anne Galy, Marisol Corral-Debrinski; Safety, local tolerability and biodistribution of GS010 (AAV2/2-ND4), a gene therapy medicinal product in development for Leber Hereditary Optic Neuropathy (LHON). Invest. Ophthalmol. Vis. Sci. 2014;55(13):3340. doi: https://doi.org/.
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LHON is a severe optic neuropathy leading to blindness and results, in most cases, from a point mutation in the mitochondrial NADH dehydrogenase subunit 4 gene (ND4). Corral-Debrinsky and Sahel’s team at Institut de la Vision in Paris demonstrated that optimized allotopic expression of GS010 rescued respiratory function of LHON fibroblasts in vitro, and restored vision in a rat model of LHON. In the present GLP study, we investigated the toxicity and biodistribution of intravitreally (IVT)-administered GS010 in non-human primates.
Cynomolgus monkeys (n=3/group/sex) received a single IVT injection of GS010 (low and high dose) or its vehicle and were sacrificed at 3 or 6 months after injection. In addition to regular systemic toxicity evaluation, local tolerability as well as local morphological and functional changes was carefully assessed using slit lamp and fundus photography, OCT-SLO imaging, IOP measurements and ocular histopathology. Persistence and shedding were evaluated in various organs and fluids.
(1) GS010 did not cause toxicity in ocular tissues and was generally well tolerated though 8/18 case of low-grade anterior uveitis were observed at the high dose at 3 months; (2) Vector DNA was essentially found in the retina and anterior segment of the eye, and was not detected in brain, gonads, cerebellum, heart, prostate, kidney, lung, ovary, seminal vesicle, testis, skin, skeletal muscle, and visual cortex; (3) ND4 mRNA was detected in retinal ganglion cells 3 months after IVT injection
The GLP toxicity and biodistribution study in non-human primate allowed to determine a well-tolerated dose and further highlighted that ND4 mRNA is expressed in retinal ganglion cells. Based on these data and extensive pharmacological studies, we expect that GS010 represents a promising treatment of LHON. In this regard, a Phase I/II clinical trial is due to start Q1 2014.
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