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Ronald BUGGAGE, Karine Bigot, Elodie Touchard, Romain Benard, Thierry Bordet, Francine F Behar-Cohen; Efficacy of EYS606 in Experimental Models of Uveitis. Invest. Ophthalmol. Vis. Sci. 2018;59(9):1191. doi: https://doi.org/.
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Tumor necrosis factor-alpha (TNF-α) is a potent mediator of intraocular inflammation. While systemic anti-TNF-α therapy has been proven as an effective treatment for uveitis, the benefit of intraocular administration of TNF-α inhibitors remains to be defined. EYS606, a plasmid encoding for a recombinant fusion protein consisting of the extracellular domain of the TNF-α p55 receptor 1 linked to the human IgG1 Fc domain, is a non-viral gene therapy based on the principle of ciliary muscle electrotransfection enabling sustained expression of therapeutic proteins in the eye. Herein, we present preclinical proof-of-concept results for EYS606 in uveitis.
Non-clinical efficacy studies were performed in the Endotoxin Induced Uveitis (EIU) and Experimental Autoimmune Uveitis (EAU) models. Uveitis was induced 3 or 6 days after EYS606 ciliary muscle injection and electrotransfection. The efficacy of EYS606 was assessed by changes in the clinical uveitis and histopathological scores relative to placebo or treated controls.
In the EIU model, EYS606 (15 µg/eye) decreased intraocular TNF-α levels by 55% and inducible nitric oxide synthase mRNA levels by 37% correlating with reduced clinical (3.4 vs 5.9 in controls) and histopathologic (3.6 vs 5.7) uveitis scores one day after disease induction. Relative to untreated controls, EYS606 (1.75 vs 3.7) was as effective as dexamethasone (1.75) and their combination (1.1) further improved this benefit. In the EAU model, EYS606 (30 µg/eye) significantly reduced clinical (2.9 vs 4.4) and histopathologic scores (9.2 vs 12.6) at day 17 following EAU induction and other timepoints tested. Anti-TNF-α protein levels (10-30 ng/mL in vitreous) achieved with a single EYS606 electroporation were as effective for reducing EAU as repeated intravitreal injections of the recombinant protein (6.5 µg/eye twice).
These results in two well-established rat models of uveitis demonstrate efficacy of EYS606 for reducing ocular inflammation and preventing retinal damage. The sustained anti-TNF-α production in the eye induced by EYS606, a minimally invasive non-viral gene delivery technology, offers a new approach for the treatment of uveitis with the potential for improved efficacy outcomes. EYS606 is currently being tested 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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