Efficacy of Intravitreal Multi-Characteristic Opsin (MCO-010) Optogenetic Gene Therapy in a Mouse Model of Leber Congenital Amaurosis.

Purpose: Leber congenital amaurosis (LCA) is a sight-threatening inherited retinal disorder (IRD) caused by numerous genetic mutations. Multi-characteristic opsin (MCO)-based optogenetic therapy allows the recruitment of residual cells of the retina in LCA for alternative vision transduction while being mutation-agnostic. Using rd12 mice, we investigated the in vivo efficacy of an adeno-associated virus2 (AAV2)-transduced ambient light-activatable MCO (MCO-010) containing a metabotropic glutamate receptor-6 bipolar cell-specific promoter/enhancer.

Methods

Mice requiring > 40 s to reach and board a dimly lit hidden platform in a water-maze were selected and randomly divided into 2 cohorts. These mice were intravitreally (IVT) injected with either 1.7E9 gene copies/eye of MCO-010 or control AAV2 and re-tested in the water-maze. Spectral-domain optical coherence tomography (SD-OCT), hematoxylin and eosin staining of retinas, and electroretinographic (ERG) studies were also conducted.

Results

Safety of MCO-010 in rd12 mice was confirmed by the lack of significant detrimental changes in the mouse behavior, b-wave amplitudes and in retinal thickness. rd12 control mice performed relatively poorly in the water-maze test requiring ≥ 30-60 s to find and board the platform. MCO-010-treated rd12 mice reached the platform much faster than the AAV2-treated rd12 mice, with some mice only requiring < 5 s to achieve this goal (P < 0.01-0.0024).

Conclusions

IVT MCO-010 treatment was well tolerated by rd12 mice, and it prevented the decrease in retinal thickness, and preserved ERG parameters. It also significantly improved the vision in rd12 mice relative to control AAV2-injected mice. MCO-010 therefore represents a novel and efficacious optogenetic therapeutic to treat LCA and other IRDs irrespective of the genetic defect(s).