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

Abstract

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.

Cone Vision Changes in the Enhanced S-Cone Syndrome Caused byNR2E3Gene Mutations

“…For example, it could result from a disturbed photoreceptor maintenance function, 40 impairment of phagocytosis due to the aberrant photoreceptors, 41 microglial proliferation, 42 and the complex interaction with modifier genes. 22 …”

“…Of relevance, these mice have been used in recent attempts at therapeutic interventions. 22 Before the present work, the diagnoses of patients, such as ESCS, Goldmann-Favre syndrome, clumped pigmentary retinopathy, and retinitis pigmentosa, have usually been listed as the human disease expressions comparable to the mouse model. 16,17,49 Based on the results of this study, more specific comparisons about disease progression can now be made between rd7 mice and patients with NR2E3 mutations.…”

“…[16][17][18][19][20] and experiments now suggest that nuclear receptors can be modulators of disease and could play a role in therapy, including the retinal degeneration resulting from NR2E3 mutations. 21,22 Given the possibility of therapy, the present study was performed using both cross-sectional and longitudinal studies of patients with NR2E3 mutations to begin to understand how this unique group of diseases could be monitored through a clinical trial intending to alter therapeutically the natural history of disease.…”

Rev‐Erbα modulates retinal visual processing and behavioral responses to light

“…Available evidence suggests an important role for Rev‐Erbα in the retina: we showed that the protein product of Rev‐Erbα complexes with the rod‐specific transcription factors neural retina leucine zipper (NRL), cone‐ rod homeobox (CRX), and nuclear receptor subfamily 2, group E, member 3 (NR2E3), which leads to additive stimulation of rhodopsin transcription (17). More recently, it was shown that small interfering RNA silencing of Rev‐ Erbα mRNA within the developing eye leads to pan‐retinal spotting and reduced amplitude of the electroretinogram (ERG) β‐wave (18), and that Rev‐Erbα expression counteracts loss of rod‐specific transcription factor Nr2e3 and prevents degeneration (19). But clear links between Rev‐ Erbα gene expression, visual processing, and behavioral responses have not yet been established.…”

Rethinking Nuclear Receptors as Potential Therapeutic Targets for Retinal Diseases

“…Finally, Nr1d1 gene delivery was also able to reregulate the key genes that are vital for photoreceptor homeostasis, which were misregulated by the absence of Nr2e3 in Nr2e3 rd7/rd7 mice. 48 This study established Nr1d1 as a potential therapeutic target that may be used as a tool for gene therapy. In addition to gene therapy, high-throughput screens for receptor ligands have identified small molecules that bind to the NR2E3.…”