Anti-sense oligonucleotide inhibitors of retinoic acid signaling and reversion of retinal remodeling for mitigating vision loss

In Retinitis Pigmentosa (RP) and age-related macular degeneration (AMD) the rod and cone photoreceptors die, depriving downstream neurons of light-sensitive input. Even though the remaining retinal circuitry remains alive and connected to the brain, the morphological and functional properties of downstream neurons change, a process known as remodeling.(1) New results suggest that remodeling plays a major role in corrupting information processing in the visual system and impairing vision, long before the photoreceptors are completely lost. While physiological remodeling is well characterized, what triggers it remained unknown--- until recently. In 2019, we reported that Retinoic Acid (RA), a metabolite of vitamin A (Fig. 2), is the signal that triggers many of the physiological changes in rd1 and rd10 mice (11), the best- studied animal models of RP. Earlier studies implicated RA in morphological remodeling in light- induced degeneration in rats. Subsequently, we showed that inhibiting various points in the RA metabolic pathway had a positive impact on improved vision in these animal models. The FDA- approved drug disulfiram (Antabuse®), an inhibitor of RALDH and other aldehyde dehydrogenases reduced hyperactive firing, as did BMS 493, an RAR inhibitor. Even more striking, disulfiram and BMS 483 mitigated vision loss in rd10 mice, assessed with behavioral tests. While effective in animal studies, both of these approaches have certain limitations as clinical treatments for RP and other aged related degenerative vision diseases, namely non- specific delivery and activity on non-retina specific pathways that may cause significant side effects. Here, we propose the development of a targeted anti-sense oligonucleotide (ASO) to block retinoic acid receptor production at the cellular level within the ocular cavity. These ASOs will be designed (and tested) to specifically block only the RAR receptor production and will be delivered locally into the ocular cavity (minimizing potential side effects in non-target organs within the body). Additionally, ASOs are long-lived once they reach target tissue and very stable in vivo (typically having in vivo half-lives in target tissue of 2-3 months), potentially making the treatment for these patients a straightforward ocular injection 2-3 times per year. During Phase 1 we will design, synthesize, and test a variety of ASO candidates in cellular assays to assess mRNA down regulation specific to RAR receptor pre-mRNA. Once candidates have been identified, they will be assessed both ex vivo and in vivo using rd10 animal models for retinal hyperactivity changes and improved vision and behavior in previously used animal models. Retinal health (of the treated animals) will be assessed prior to sacrifice and in vivo confirmation of mRNA knockdown.