Ambient light activatable opsin based therapy for age-related macular degeneration

Severe loss of vision occurs due to retinal degeneration as in dry age-related macular degeneration (dry-AMD) in which dysfunction of retinal cells occurs leading to blocking of the visual transduction cycle. Retinal prostheses offer the possibility of restoring limited vision. Current systems, however, are limited by poor resolution, retinal damage over time. Optogenetic sensitization of retinal cells has potential as an interim solution until the regenerative medicine is successful. In addition to higher resolution, optogenetics has advantages such as cellular specificity and minimally invasive intravitreal injection. With advent of Ambient- light activatable, fast and broadband Multi-Characteristic Opsin (MCO), the hurdle in clinical translation of optogenetic vision restoration is removed. The phase-II SBIR support has enabled us to complete rigorous IND-enabling pre-clinical studies including evaluation of efficacy, pharmacokinetics and GLP toxicity and Biodistribution of intravitreally-injected vMCO in small and large animals. These studies were guided by inputs from FDA during our pre-IND meeting and follow-up communications. Our phase-II SBIR studies demonstrate that process-developed vMCO remains stable and potent for rt 1 year leading to the efficient expression in bipolar cells. MCO-dose dependent expression was highly correlated with improved visually guided behavior in radial water maze and optomotor response at ambient light illumination. Further, we found intravitreal injection of vMCO drives MCO expression in bipolar cells of two different mice models of retinal degeneration and large animals. The safety of vMCO in mice was confirmed by no detectable retinal phototoxicity after chronic exposure with intense light for four months. Further, no significant increase of pro and anti- inflammatory cytokines in plasma or vitreous humor was observed six months after vMCO injection. Based on this success and feedback from FDA, we aim to further develop the product (vMCO) for restoring vision in dry- AMD subjects with retinal dystrophies in ambient light environment. The objective of this phase-IIb SBIR project will be accomplished through three aims. Aim 1: Robust controlled production of vMCO with high yield and comparable performance; Aim 2: Evaluation of transduction efficacy and visual function using electrophysiology in dry-AMD model of NHPs; and Aim 3: A Phase 1 Open Label, Dose-Escalation Study to Evaluate the Safety and Tolerability of Intraocular vMCO injection in Patients with Advanced dry-AMD. This collaborative effort brings together complementary expertise to address a challenging problem in retinal degenerative diseases. Upon completion of the phase IIb SBIR we envision to advance: (i) Initiation of Phase- 2 trial for evaluating efficacy, and (ii) enhance our partnership with private-equity/venture capital firms and pharmaceutical company for commercialization. Success of this proposal will lead to a new clinical approach for treating patients with dry-AMD at ambient light. This gene-agnostic approach will allow treatment of other retinal degenerative diseases such as retinitis pigmentosa, Stargardt and cone-rod dystrophy.