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Neena B. Haider, Yang Yuan, Nissa Mollema, Barrett Leehy, Rinku Baid, Uday B. Kompella; Rescue of Nr2e3 Associated Retinal Degeneration Using Nanoparticle Based Gene Delivery. Invest. Ophthalmol. Vis. Sci. 2011;52(14):431.
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Mutations in the nuclear hormone receptor gene NR2E3 are associated with several human retinal diseases that result in degeneration of rod and cone photoreceptors. NR2E3 has been shown to be a key factor in regulating retinal progenitor cells to produce the appropriate number of blue cones and also in directing proper rod cell differentiation. The purpose of this study is to determine the efficacy of nanoparticle based Nr2e3 gene delivery to rescue Nr2e3 associated retinal diseases. We also evaluated the efficiency of mechanism of delivery with and without electroporation.
Biodegradable poly(lactide-co-glycolide) nanoparticles encapsulating pNr2e3 were introduced into postnatal day 0 (P0) rd7 retinas (lacking a functional NR2E3 protein) (n=6) with and without electroporation. Treated animals were examined at 2 and 6 months for alterations in their clinical, histological, and morphological phenotype using indirect ophthalmoscopy, hematoxylin/eosin staining, immunohistochemistry, and electroretinography(ERG), respectively.
Mutant rd7 retinas treated with Nr2e3 nanoparticles exhibited clinical improvements with the disappearance of the characteristic rd7 spotted retina and morphologically with rescue of rd7 associated whorls and rosettes. ERG analysis showed a significantly improved amplification of both a and b wave of the treated eyes compared to the reduced function observed in untreated rd7 eyes. Finally, rescue of rd7 associated retinal degeneration was attained in both electroporated and nonelectroporated Nr2e3 nanoparticle treated mutant eyes.
Nanoparticle delivery of Nr2e3 in the rd7 mice efficiently ameliorated clinical, morphological, and functional defects associated with rd7 retinal degeneration. Further, evaluation of the efficacy of delivery with and without electroporation demonstrated that particles are able to enter and function in the retina effectively without electroporation.
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