| Experiment Id | GSE286529 | Name | Reactivating the phototransduction cascade with a mutation agnostic gene therapy preserves vision in Rod-Cone Dystrophies |
| Experiment Type | RNA-Seq | Study Type | WT vs. Mutant |
| Source | GEO | Curation Date | 2025-01-21 |
| description | Rod-cone dystrophy (RCD), or retinitis pigmentosa, involves genetic conditions where rod degeneration precedes cone degeneration, resulting in tunnel vision and eventual blindness. Previous studies attempted to restore cone activity and prolong vision by expressing microbial chloride pumps in degenerating cone photoreceptors. However, microbial opsins require high expression and intense light, limiting their effectiveness. In this work, we explored the phototransduction cascade in degenerating cones in two RCD mouse models. We observed that opsin and arrestin expression persists in the soma during outer segment degeneration. This led us to hypothesize that reactivating cones based on cone opsin signaling may be possible by expressing a target channel activated by G proteins recruited by cone opsin. Through adeno-associated viral (AAV) mediated expression of the G protein-coupled inwardly rectifying K (GIRK) channel, we achieved improvements in visual function in two RCD mouse models with mutations in different genes. Importantly, we validated the rationale of GIRK-mediated gene therapy in humans by confirming cone opsin and cone arrestin expression in cones of late-stage RCD patients. Our proposed approach involves GIRK channel expression in cones as a novel method to maintain high acuity, sensitivity, and color vision in RCD, independent of the underlying mutation. Single-cell RNAseq of rd10 retinas from six mice at PND126 and rd1 retinas from five rd1 mice at PND112-PND116. Cells from rd10 and rd1 retinas were pooled into two and three samples, respectively. |
