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-Erba) 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.