title: Potential of Small Molecule-Mediated Reprogramming of Rod Photoreceptors to Treat Retinitis Pigmentosa.
abstract: Mutations in rod photoreceptor genes can cause retinitis pigmentosa (RP). Rod gene expression is regulated by the nuclear hormone receptor, Nr2e3. Genetic deletion of Nr2e3 reprograms rods into cells that resemble cone photoreceptors, and might therefore prevent their death from some forms of RP. There are no identified ligands for Nr2e3; however, reverse agonists might mimic the genetic rescue effect and may be therapeutically useful for the treatment of RP.
  
  
  
  We screened for small molecule modulators of Nr2e3 using primary retinal cell cultures and characterized the most potent, which we have named photoregulin1 (PR1), in vitro and in vivo. We also tested the ability of PR1 to slow the progression of photoreceptor degeneration in two common mouse models of autosomal dominant RP, the RhoP23H and the Pde6brd1 mutations.
  
  
  
  In developing retina, PR1 causes a decrease in rod gene expression and an increase in S opsin+ cones. Photoregulin1 continues to inhibit rod gene expression in adult mice. When applied to two mouse models of RP, PR1 slows the degeneration of photoreceptors.
  
  
  
  Chemical compounds identified as modulators of Nr2e3 activity may be useful for the treatment of RP through their effects on expression of disease-causing mutant genes.
authors.affiliation: Department of Biological Structure, University of Washington, School of Medicine, Seattle, Washington, United States.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Nakamura
authors.affiliation: University of California-San Francisco, UCSF School of Pharmacy, Department of Pharmaceutical Chemistry, San Francisco California, United States.
authors.forename: Shibing
authors.initials: S
authors.lastname: Tang
authors.affiliation: Department of Biological Structure, University of Washington, School of Medicine, Seattle, Washington, United States.
authors.forename: Andy A
authors.initials: AA
authors.lastname: Shimchuk
authors.affiliation: University of California-San Francisco, UCSF School of Pharmacy, Department of Pharmaceutical Chemistry, San Francisco California, United States.
authors.forename: Sheng
authors.initials: S
authors.lastname: Ding
authors.affiliation: Department of Biological Structure, University of Washington, School of Medicine, Seattle, Washington, United States.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Reh
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D002478:Cells, Cultured; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6 / Q000235:genetics / Q000378:metabolism; D004247:DNA / Q000235:genetics*; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D018507:Gene Expression Regulation, Developmental; D020287:In Situ Nick-End Labeling; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D057093:Orphan Nuclear Receptors / Q000096:biosynthesis / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D012160:Retina / Q000378:metabolism* / Q000473:pathology; D017949:Retinal Cone Photoreceptor Cells / Q000378:metabolism* / Q000473:pathology; D017948:Retinal Rod Photoreceptor Cells / Q000378:metabolism* / Q000473:pathology; D012174:Retinitis Pigmentosa / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D046509:Tissue Culture Techniques
chemical_list: C485736:Nr2e3 protein, mouse; D057093:Orphan Nuclear Receptors; D004247:DNA; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; C517438:Pde6b protein, mouse