Abstract
Purpose :
In this study, we evaluated the role of OCU410 (human RORA) as a modifier gene therapy candidate in regulating inflammation, lipid metabolism, phagocytosis, and cellular redox potential for dry age-related macular degeneration (dry-AMD) therapy in in-vitro assays. While there is no approved therapy for dry AMD, most therapeutics in clinical trials target only one pathway such as the complement system (cell death pathway), inflammation, or oxidative stress. This may have limitations in achieving optimal therapeutic benefit specifically in the case of dry AMD which is a complex and multifactorial disease. OCU410 is an orphan nuclear receptor, a transcription factor, that may target multiple pathways benefiting the retina in the event of dry AMD
Methods :
In-vitro cellular model system was used to access the beneficial effects of OCU410 that might control multiple aspects of cellular physiology beneficial for the retina. Various cell and molecular biology techniques like gene expression analysis using RNA-Seq, RT-qPCR, phagocytosis assay, cell survival assays, and promoter-reporter assays were used to monitor the role of OCU410 under different experimental conditions.
Results :
Our results demonstrate that OCU410 regulates various cellular physiological processes relevant to the health of retinal cells that are important in dry AMD. OCU410 suppresses the expression of inflammatory cytokines, promotes cell survival in the event of oxidative stress, inhibits complement factors, and modulates phagocytosis by retinal pigment epithelial cells. Overall, our results suggest that OCU410 modulates various cellular processes that impart beneficial effects to retinal cells and help in putting a tab on the progression of dry-AMD
Conclusions :
Dry-AMD is characterized by the expression of inflammatory cytokines. OCU410 transduction leads to the expression of nuclear hormone receptor RORA upon viral transduction which suppresses inflammatory cytokine gene expression, inhibits complement factor activation, modulates cellular phagocytosis, and promotes cell survival from oxidative stress. Thus, OCU410’s ability to inhibit multiple cellular physiology strengthens its potential as a gene therapy molecule for dry AMD.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.