April 2014
Volume 55, Issue 13
ARVO Annual Meeting Abstract  |   April 2014
Nuclear Hormone Receptors are Potent Genetic Modifiers that Rescue Multiple Models of Retinal Degeneration
Author Affiliations & Notes
  • Neena B Haider
    Dept of Ophthalmology, Schepens Eye Research Inst/MEEI, Boston, MA
  • Ana B Olivares
    Dept of Ophthalmology, Schepens Eye Research Inst/MEEI, Boston, MA
  • Nelly M Cruz
    Dept of Ophthalmology, Schepens Eye Research Inst/MEEI, Boston, MA
  • Pascal Escher
    Ophthalmology, Institute for Research in Ophthalmology, Lausanne, Switzerland
  • Margaret M DeAngelis
    Ophthalmology, University of Utah, Salt Lake City, UT
  • Footnotes
    Commercial Relationships Neena Haider, None; Ana Olivares, None; Nelly Cruz, None; Pascal Escher, None; Margaret DeAngelis, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science April 2014, Vol.55, 2182. doi:
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      Neena B Haider, Ana B Olivares, Nelly M Cruz, Pascal Escher, Margaret M DeAngelis; Nuclear Hormone Receptors are Potent Genetic Modifiers that Rescue Multiple Models of Retinal Degeneration. Invest. Ophthalmol. Vis. Sci. 2014;55(13):2182.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose: Retinal degeneration affects 1 in 1000 individuals world wide and most often results in loss of rod or cone photoreceptor cells. Our prior studies demonstrated the critical role of the nuclear hormone receptor genes Nr2e3 and Nr1d1 in modulating proper development and function of photoreceptor cells. The goal of this study was to determine whether either or both Nr2e3 and Nr1d1 can rescue retinal degeneration in models where the primary mutation lies in genes within their regulated gene networks.

Methods: Neonatal rd1-/-, rd10-/-, rhodopsin-/-, and rd7-/- mice were injected subretinally with AAV or nonviral plasmids for Nr2e3 or Nr1d1. Clinical and phenotypic characterization of the injected eyes were performed at postnatal day 30 (P30) using the following analyses: indirect ophthalmoscopy, electroretinogram, histology and immunohistochemistry. ChIP-seq was performed to identify all targets of Nr2e3 and Nr1d1. Highly regulated target genes were evaluated in the injected eyes and compared to uninjected to examine molecular rescue of the Nr2e3 and Nr1d1 modulated gene networks.

Results: We evaluated several models of retinal degenerations that exhibit mild to severe photoreceptor loss: rd1-/-, rd10-/-, rhodopsin-/-, and rd7-/-. Both Nr2e3 and Nr1d1 were able to the rescue clinical, histological, and functional defects from mild to severe forms of retinal degeneration. Furthermore, the mechanism of rescue is through re-regulation of the transcriptional network regulated by these nuclear hormone receptors.

Conclusions: The nuclear hormone receptors Nr2e3 and Nr1d1 are potent genetic modifiers that rescue retinal degeneration. These nuclear hormone receptor genes can rescue not only mild but also severe forms of retinal degeneration. They function by modulating gene networks and pathways crucial for normal photoreceptor development and function. This study demonstrates the significance of nuclear hormone receptors in gene therapy. The study also strongly indicates the use of genetic modifier genes to treat many forms of retinal disease.

Keywords: 538 gene transfer/gene therapy • 696 retinal degenerations: hereditary • 648 photoreceptors  

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