Modifier genes as therapeutics: the nuclear hormone receptor Rev Erb alpha (Nr1d1) rescues Nr2e3 associated retinal disease.
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.
Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, United States of America ; Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States of America.
Nelly M
NM
Cruz
Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
Yang
Y
Yuan
Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, United States of America.
Barrett D
BD
Leehy
Nanomedicine and Drug Delivery Laboratory, Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.
Rinku
R
Baid
Nanomedicine and Drug Delivery Laboratory, Department of Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America ; Department of Ophthalmology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.
Uday
U
Kompella
Ophthalmology and Visual Sciences, John A. Moran Eye Center, Center for Translational Medicine, University of Utah, Salt Lake City, Utah, United States of America.
Margaret M
MM
DeAngelis
Institute for Research in Ophthalmology, Grand-Champsec Sion, Switzerland.
Pascal
P
Escher
Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, United States of America ; Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts, United States of America.
Neena B
NB
Haider
D000818:Animals; D015785:Eye Diseases, Hereditary / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1 / Q000096:biosynthesis / Q000235:genetics; D057093:Orphan Nuclear Receptors / Q000096:biosynthesis / Q000235:genetics; D012162:Retinal Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D012174:Retinitis Pigmentosa / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D014786:Vision Disorders / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy
C403073:NR2E3 protein, human; C498262:Nr1d1 protein, mouse; C485736:Nr2e3 protein, mouse; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D057093:Orphan Nuclear Receptors