Abstract
Purpose :
Leber congenital amaurosis (LCA) is a sight-threatening inherited retinal disorder caused by dozens of different gene mutations in proteins that catalyze many of the series of enzymatic reactions to generate 11-cis retinal from vitamin A (visual cycle). Use of multi-characteristic opsin (MCO)-based optogenetic therapy leverages existing cells of the retina for alternative vision transduction while being mutation-agnostic and not requiring presence of dysfunctional outer retinal cells. Using an animal model of LCA (B6(A)-Rpe65rd12/J mice [RPE65]) we investigated the in vivo efficacy of an adeno-associated virus2 (AAV2)-transduced ambient light-activatable MCO (MCO-010) under control of an mGluR6 promoter-enhancer.
Methods :
RPE65 mice (>16 weeks old) were tested in a radial water-maze for their ability to locate and board a distant platform which provided a white light visual cue, and the time to accomplish this task was recorded. The same mice then received an intravitreal injection of MCO-010 (1.14E9 gene copies/eye) to transduce retinal ON bipolar cells. Four-six weeks after MCO-010 injection, the MCO-010-treated mice were tested again in the water-maze. Additional studies utilized spectral domain optical coherence tomography (SDOCT) and electroretinogram analyses to determine the retinal thickness and retinal function (ERG), respectively.
Results :
RPE65 mice performed relatively poorly in the water-maze test. Thus, naïve RPE65 mice were screened to select those requiring >40 seconds to reach and board the platform. Unlike the vehicle-treated RPE65 mice, the MCO-010-treated mice reached the platform significantly faster than the untreated mice (p < 0.0026; n = 5/group). Longitudinal monitoring of retinas of RPE65 mice with SDOCT showed stabilization of retinal thickness in MCO-010-injected group, while the control group exhibited a steady decline in retinal thickness commensurate with their vision loss.
Conclusions :
The MCO-010 treatment was well tolerated by LCA-harboring mice. Furthermore, this gene therapy significantly attenuated retinal cell loss in the RPE65 mice and restored their vision as judged by structural and functional activity parameters described above. MCO-010 therefore represents a useful therapeutic modality for improving visual outcomes in this LCA animal model.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.