Name

Électrotransfert de plasmides dans le muscle ciliaire pour le traitement des maladies rétiniennes

Delivering active drug levels to the back of the eye still remains a challenge. 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 of the ciliary muscle which serves as a biofactory for sustained production of therapeutic proteins in the eye. This innovative drug delivery platform has the potential to address major unfulfilled needs in the treatment of sight threatening ophthalmic diseases. Herein, we present preclinical proof-of-concept and non-clinical safety results for EYS606, a plasmid encoding for a potent chimeric soluble TNF-a receptor, to support its development for treatment of non-infectious uveitis.

Efficacy of EYS606 was assessed in the Endotoxin Induced Uveitis (EIU) and Experimental Autoimmune Uveitis (EAU) rat models by changes in the clinical uveitis and histopathological scores relative to placebo or treated controls. Non-clinical safety, local tolerance, plasmid biodistribution, and transgene expression were evaluated in rabbits at two different doses (45 µg and 142.2 µg/eye) for up to 3-months.

In the EIU model, EYS606 (15 µg/eye) decreased intraocular TNF-a levels by 55% correlating with reduced clinical and histopathologic uveitis scores one day after disease induction. Relative to untreated controls, EYS606 was as effective as dexamethasone and their combination further improved this benefit. In the EAU model, EYS606 (30 µg/eye) significantly reduced clinical and histopathologic scores (2.9 vs 4.4 and 9.2 vs 12.6, respectively) at day 17 following EAU induction. Anti-TNFα protein levels (10-30 ng/mL in vitreous) achieved with a single EYS606 administration were as effective for reducing EAU as repeated intravitreal injections of the recombinant protein (6.5 µg/eye twice). EYS606 electrotransfection was safe in rabbits. Plasmid distributed in the ciliary muscle with persistence up to 3-months but only transiently in surrounding ocular tissues. Plasmid distribution in blood and in peripheral organs was found only anecdotally in some rabbits treated with the highest dose with no persistence over time. Similarly, the anti-TNF-a protein encoded by EYS606 was detected up to 3-months in the vitreous with only minimal leakage in serum at day 6 following electrotransfection.

These results demonstrate the safety of plasmid electroporation in the ciliary muscle using a minimally invasive device to turn the eye into a biofactory for the treatment of retinal diseases. The efficacy of EYS606 in two well-established rat models of uveitis with sustained anti-TNF-a protein secretion offers a new approach for the treatment of uveitis with the potential for improved efficacy outcomes. 

Beyond the promise of our lead candidate EYS606, this novel gene therapy strategy opens new therapeutic avenues for diseases with still unmet medical need such as Retinitis Pigmentosa, early stage Geographic Atrophy, or glaucoma.