Multi-characteristic opsin gene therapy attenuates retinal degeneration and restore vision in mouse models of retinitis pigmentosa

Abstract

Purpose : Retinitis pigmentosa (RP) causes vision loss due to progressive retinal degeneration. This study evaluated whether sensitization of inner retina by multi-characteristic opsin could attenuate structural retinal degeneration while restoring vision function in mouse models of RP.

Methods : AAV2 packaged ambient light activatable MCO (MCO-010) was used to sensitize bipolar cells in animal models of retinitis pigmentosa. MCO-010 (3.4E6 to 3.4E9 gc/eye) was intravitreally delivered to rd1 mice (rapid degeneration) and rd10 mice (slower degeneration). Longitudinal measurement of retinal thickness was conducted by OCT. Immunohistochemical (IHC) analysis assessed the structural integrity axonal terminals of bipolar cells. Vision function was assessed by optomotor response, electrophysiology, and radial arm water maze assay.

Results : Robust MCO-010 expression was observed in ~70% of bipolar cells upon intravitreal administration. In contrast to AAV2 vehicle controls, MCO-010 expression in inner retina of rd mice significantly attenuated further thinning (measured by OCT). No statistically significant difference in retinal thickness was observed for MCO-010 treated groups over time (N=10/group), whereas the vehicle injected group (N=10/group) showed significant retinal thinning compared to baseline at 4-month timepoint. The bipolar cell synaptic terminals were found to be preserved in MCO-010 treated group as measured by IHC using CtBP and PKCa marker. Radial water maze behavior assay and optomotor assessment showed significant improvement of vision upon MCO-010 treatment.

Conclusions : Intravitreal MCO-010 treatment enabled durable restoration of visual behavior in ambient light in mouse models of RP. Notably, attenuation of progressive structural retinal degeneration was observed on OCT and IHC analysis. This structural preservation combined with functional gains supports disease-modifying potential for MCO-based optogenetic therapies in advanced retinal degeneration.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.