Abstract
Purpose :
Inherited Retinal Disorders (IRDs) such as Stargardt disease (SD) or Leber congenital amaurosis (LCA) are rare, and sight-threatening with significant unmet needs. In these IRDs, dysfunction or degeneration of photoreceptors leads to loss of light sensitivity. Optogenetics offers a unique opportunity to treat IRDs of varied genetic origins with a universal therapeutic strategy. The purpose of the study is to evaluate the therapeutic efficacy of intravitreally delivered AAV2-carried gene encoding for ambient light-activatable Multi-Characteristic Opsin (MCO) in animal models of SD and LCA.
Methods :
To evaluate the therapeutic efficacy, AAV2-MCO (vMCO) was intravitreally delivered in mice models of SD (Abca4tm1Ght/J) and LCA (B6(A)-Rpe65rd12/J). OCT imaging of the retina, behavioral assay (water maze), and ERG were performed longitudinally up to 24 weeks to evaluate the safety and efficacy of the treatment. Immunohistochemistry of the retina sample was also performed to visualize the expression of MCO in the retina (Visualized by mCherry expression).
Results :
Our results demonstrated that intravitreal delivery of vMCO to Stargardt and LCA mice arrests further retinal degeneration (measured by retina thickness using OCT) and restores visual function, quantified by electrophysiology of retina (ERG) and visual cortex (VEP). The visually- guided water maze assessment on vMCO-treated mice showed significant improvement (measured by latency to reach platform) as compared to the vehicle-injected control mice group.
Conclusions :
vMCO is potentially a restorative treatment that can be used irrespective of the underlying gene mutation. Intravitreal delivery of vMCO in the Stargardt and LCA mice model was effective in restoring vision and arresting further retinal degeneration. While the efficacy of MCO optogenetic monotherapy is now being evaluated in a multicenter trial on advanced Retinitis Pigmentosa patients, clinical evaluation of vMCO for other IRDs will establish it as an outer retinal degenerative disease-agnostic therapy.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.