OCU410 (RORA-AAV) is a second in-line modifier gene therapy being developed for the treatment of dry age-related macular degeneration (Dry AMD). OCU410, gene therapy, utilizes AAV delivery platform for retinal delivery of RORA gene (RAR Related Orphan Receptor A). Various genes associated with AMD, Fms related tyrosine kinase 1(Flt1), the receptor for vascular endothelial growth factor (VEGF), and ATP binding cassette subfamily A member 1 (Abca1) are regulated by NR2E3 and RORA. Besides this, RORA plays an important role in lipid metabolism (apolipoproteins APOA1, APOA5, APOC3 and PPARG), and demonstrate anti-inflammatory role by inducing CHUK expression and inhibiting NF-kappa-B signaling.
AMD is characterized by thickening and loss of normal architecture within Bruch’s membrane, lipofuscin accumulation in the RPE, and drusen formation beneath the RPE in Bruch’s membrane. These deposits consist of complement components, other inflammatory molecules, lipids, lipoproteins B and E, and glycoproteins. Based on RORA role in lipid metabolism and inflammation it is assumed that it could be a potential therapeutic candidate for Dry AMD.
About Age-Related Macular Degeneration
Age-related macular degeneration (AMD) is a leading cause of irreversible blindness in the world. Approximately 11 million individuals are affected with AMD in the United States alone, with a global prevalence of 170 million. AMD pathology is characterized by degeneration involving the retinal photoreceptors, retinal pigment epithelium, and Bruch’s membrane. Currently, there is no approved treatment dry-AMD, which accounts for 85-90% of the total AMD population.
- Olivares, a. M. et al. Multimodal Regulation Orchestrates Normal and Complex Disease States in the Retina /631/114/2114. Scientific Reports 7, 1-16, doi:10.1038/s41598-017-0788-3 (2017).
- Jun, G. et al. Influence of ROBO1 and RORA on Risk of Age-Related Macular Degeneration Reveals Genetically Distinct Phenotypes in Disease Pathophysiology. PLoS ONE 6, doi:10.1371/journal.pone.0025775 (2011).
- Katie L. Pennington and Margaret M. DeAngelis. Epidemiology of age-related macular degeneration (AMD): associations with cardiovascular disease phenotypes and lipid factors. Eye Vis (Lond). 2016; 3: 34.
- Xiaoyan Ding, Mrinali Patel, and Chi-Chao Chana. Molecular pathology of age-related macular degeneration. Prog Retin Eye Res. 2009 Jan; 28(1): 1-18.
- Silveira, AC. et al. Convergence of linkage, gene expression and association data demonstrates the influence of the RAR-related orphan receptor alpha (RORA) gene on neovascular AMD: a systems biology based approach. Vision Res. 2010 Mar 31;50(7):698-715.
- Sun, Y et al. Nuclear receptor RORα regulates pathologic retinal angiogenesis by modulating SOCS3-dependent inflammation. Proc Natl Acad Sci U S A. 2015 Aug 18;112(33):10401-6.