A modified Arrestin1 Slows Retinal Degeneration Across Genetically Distinct Mouse Models of Inherited Retinal Disease

Inherited retinal diseases (IRDs) are a genetically heterogeneous group of disorders caused by mutations in more than 340 genes, limiting the applicability of gene-targeted therapies and creating the need for broader treatment strategies. Photoreceptor dysfunction is a hallmark of IRDs and often results in disrupted retinal metabolic homeostasis, as photoreceptors have exceptionally high metabolic demands and provide metabolic resources to surrounding retinal cells. Consequently, enhancing retinal metabolism has emerged as a promising gene-agnostic strategy for treating IRDs. We previously developed a modified arrestin1 (ArrGG) that relieves arrestin1-mediated inhibition of the glycolytic enzyme enolase1, thereby increasing glycolytic output and slowing retinal degeneration in the RhoP23H/+ mouse model. Here, we investigated the therapeutic potential of ArrGG as a gene-agnostic approach targeting endogenous metabolic enzyme activity across genetically distinct models of IRD. Using two complementary photoreceptor-enriched transcriptomic analyses, we found no widespread, reproducible transcriptional changes following ArrGG treatment. These findings support our hypothesis that ArrGG modulates photoreceptor metabolism without inducing substantial transcriptional remodeling. The therapeutic efficacy of ArrGG was evaluated in three IRD mouse models representing rapid rod degeneration (rd10), cone degeneration (GC1KO), and RPE-associated retinal degeneration (rd6). ArrGG treatment was associated with preserved retinal function and slowed structural degeneration across all three models. Together, these findings support the potential of modulating endogenous metabolic enzyme activity to preserve photoreceptors across genetically distinct IRD models. This work suggests that ArrGG could be a promising gene-agnostic metabolic therapy for slowing retinal degeneration and preserving visual function in inherited retinal diseases.