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Neena B Haider, Ana Maria Olivares, Kyle Flattery, Yinan Han, Jessica Capri, Margaret M DeAngelis; Master Modifier Nr2e3 Rescues Disease and Promotes Retina Homeostasis in Multiple Models of RP. Invest. Ophthalmol. Vis. Sci. 2017;58(8):1575.
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© ARVO (1962-2015); The Authors (2016-present)
Inherited retinal diseases are a large group of genetically heterogeneous disorders that when considered as a whole, are the leading cause of blindness in the world. These diseases include syndrominc and nonsyndromic forms of retinitis pigmentosa (RP) that affect one in every 1000 individuals worldwide. Currently, there is no cure for RP and over 40% of RP cannot be genetically diagnosed. RP is heterogeneous and varies greatly in age of onset, rate of progression, and even genetic etiology, yet a common pathology of photoreceptor (PR) cell degeneration develops. Our lab has shown that phenotypic outcome results from a mutational load on a biological system that includes the primary mutation and other factors such as modifier alleles impacting the normal homeostatic state. The goal of this study was to determine the efficacy of Nr2e3 as a master regulator in preventing and attenuating RP disease in multiple models.
Neonatal and developed rd1-/-, Rho -/-, Cep290-/-, RhoP23H, Arr1 -/- and rd7 -/- mice were injected subretinally with AAV Nr2e3. Clinical and phenotypic characterization of the injected eyes was performed at 3 months age by indirect ophthalmoscopy, electroretinogram, histology and immunohistochemistry. Gene expression of the treated and control eyes were evaluated through quantitative real time PCR to determine the gene networks by which Nr2e3 rescues RP disease.
Therapeutic delivery of Nr2e3 rescued and/or attenuated retinal degeneration in multiple models of RP. Clinical, histological and functional rescue was observed in all the models tested. Gene expression analysis showed that key networks such as metabolism, phototransduction and inflammation were reset towards normal in the treated compared to control eyes.
The nuclear hormone receptor Nr2e3 is a potent genetic modifier that can rescue RP associated retinal disease in the presence of the primary mutation. Nr2e3 can also attenuate disease in early-intermediate phases of RP disease; and as such is a strong therapeutic target that re-regulates biological pathways necessary for the development and maintenance of photoreceptors. This study has strong potential for novel therapeutics to treat RP disease, especially in cases where the primary mutation is not easily identified.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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