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Thierry Bordet, Karine Bigot, Romain Benard, Jean-Denis Laffitte, Elodie Touchard, Ronald Buggage, Francine F Behar-Cohen; Non-Clinical Safety of Ciliary Muscle Electrotransfection. Invest. Ophthalmol. Vis. Sci. 2018;59(9):5679. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Development of new retinal disease treatments are limited due to the challenge of delivering active drug levels to the back of the eye. While systemic therapies deliver low drug concentrations in the eye, intravitreal approaches requiring frequent injections or invasive techniques raise compliance and safety concerns. To overcome such limitations, we have developed a non-viral gene therapy strategy based on the electrotransfection (ET) of the ciliary muscle (CM) which serves as a biofactory for sustained production of therapeutic proteins in the eye. Herein, we present results of a study evaluating the safety and biodistribution of EYS606, a DNA plasmid coding for a potent soluble TNF-a receptor.
A total of 54 New Zealand White rabbits were allocated to two treated groups (45 µg and 142.2 µg/ eye) and one control group Treated groups received a single intraciliary muscle administration of EYS606 followed by ET. Animals were sacrificed on Day 6 (D6), D30 or D90.
No mortality, abnormal clinical signs, alteration in body weight, body temperature nor food intake were observed and no clinically relevant changes in blood chemistry, hematology nor relevant microscopic findings were found in treated rabbits compared to controls. EYS606 intraciliary muscle injection and the ET procedure did not cause any adverse ocular effects. On D6, the plasmid distributed almost exclusively in the CM and transiently in surrounding ocular tissues (anterior segment, optic chiasm, optic nerve, retina, vitreous and aqueous humors) with persistence up to D90 only in the CM. The plasmid distribution in blood and in peripheral organs was found anecdotally on D6 at very low levels (3- to 4-log less than in CM) in some rabbits treated with the highest dose, with no persistence on D90. Similarly, the anti-TNF-a protein encoded by EYS606 was detected only on D6 in serum but up to D90 in the vitreous.
Our results demonstrate the safety of EYS606 administered using a minimally invasive proprietary system for ciliary muscle injection and electrotransfection. Following a single administration EYS606 was localized primarly in the ciliary muscle, whereas, its induced anti-TNF-a protein was detectable up to 3 months in all the compartments of the eye. These safety findings support the further clinical development of EYS606 in patients suffering from non-infectious uveitis (NCT03308045).
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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