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Potential of Small Molecule-Mediated Reprogramming of Rod Photoreceptors to Treat Retinitis Pigmentosa
- Source :
- Investigative Ophthalmology & Visual Science
- Publication Year :
- 2016
-
Abstract
- Purpose 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. Methods 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. Results 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. Conclusions 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.
- Subjects :
- 0301 basic medicine
Opsin
retina
genetic structures
Mutant
Blotting, Western
DNA Mutational Analysis
medicine.disease_cause
Real-Time Polymerase Chain Reaction
Tissue Culture Techniques
03 medical and health sciences
Mice
Retinal Rod Photoreceptor Cells
transcription factors
Gene expression
Retinitis pigmentosa
medicine
In Situ Nick-End Labeling
Animals
Cells, Cultured
Genetics
Mutation
Retina
Cyclic Nucleotide Phosphodiesterases, Type 6
Gene therapy of the human retina
biology
Gene Expression Regulation, Developmental
reprogramming
DNA
medicine.disease
Orphan Nuclear Receptors
eye diseases
3. Good health
Cell biology
Mice, Inbred C57BL
Disease Models, Animal
030104 developmental biology
medicine.anatomical_structure
Animals, Newborn
Retinal Cell Biology
Rhodopsin
biology.protein
Retinal Cone Photoreceptor Cells
retinal degeneration
sense organs
Retinitis Pigmentosa
Subjects
Details
- ISSN :
- 15525783
- Volume :
- 57
- Issue :
- 14
- Database :
- OpenAIRE
- Journal :
- Investigative ophthalmologyvisual science
- Accession number :
- edsair.doi.dedup.....d80bd8b6a07e47b7282a80c105e6951a