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Nuclear hormone receptors play a major role in many important biological processes. Most nuclear hormone receptors are ubiquitously expressed and regulate processes such as metabolism, circadian function, and development. They function in these processes to maintain homeostasis through modulation of transcriptional gene networks. In this study we evaluate the effectiveness of a nuclear hormone receptor gene to modulate retinal degeneration and restore the integrity of the retina. Currently, there are no effective treatment options for retinal degenerative diseases leading to progressive and irreversible blindness. In this study we demonstrate that the nuclear hormone receptor gene  Nr1d1  ( Rev-Erbα ) rescues  Nr2e3- associated retinal degeneration in the  rd7  mouse, which lacks a functional  Nr2e3  gene. Mutations in human  NR2E3  are associated with several retinal degenerations including enhanced S cone syndrome and retinitis pigmentosa. The  rd7  mouse, lacking  Nr2e3 , exhibits an increase in S cones and slow, progressive retinal degeneration. A traditional genetic mapping approach previously identified candidate modifier loci. Here, we demonstrate that  in vivo  delivery of the candidate modifier gene,  Nr1d1  rescues  Nr2e3  associated retinal degeneration. We observed clinical, histological, functional, and molecular restoration of the  rd7  retina. Furthermore, we demonstrate that the mechanism of rescue at the molecular and functional level is through the re-regulation of key genes within the  Nr2e3 -directed transcriptional network. Together, these findings reveal the potency of nuclear receptors as modulators of disease and specifically of NR1D1 as a novel therapeutic for retinal degenerations.

Modifier Genes as Therapeutics: The Nuclear Hormone Receptor Rev Erb Alpha (Nr1d1) Rescues Nr2e3 Associated Retinal Disease