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Nelly M. Cruz, Yang Yuan, Rinku Baid, Uday Kompella, Neena B. Haider; Efficacy of Nanoparticle-based Gene Delivery for Rescuing Nr2e3 Associated Retinal Degeneration. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1884.
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The nuclear hormone receptor Nr2e3 is a retinal-specific transcription factor with critical functions in photoreceptor cell development and differentiation. Mutations in NR2E3 have been associated with several eye disorders characterized by progressive retinal degeneration, such as Enhanced S-cone syndrome (ESCS) and Retinitis Pigmentosa. Currently, there are no effective treatment options for this group of diseases. In order to develop a therapeutic strategy for Nr2e3-associated retinal degeneration, we are using biodegradable Nile red poly(lactide-co-glycolide) (PLGA) nanoparticles to deliver the Nr2e3 gene into retinal degeneration 7 (rd7) mouse, which lacks Nr2e3 expression.
Nr2e3 loaded Nile red PLGA nanoparticles were introduced into postnatal day 0 (P0), P10 or P21 rd7 eyes by intravitreal or subretinal injection, followed by electroporation. The efficacy of delivery was assessed using Nile red as a nanoparticle tracking dye, and green fluorescent protein expression as a marker of transfected cells. To determine the effectiveness of the Nr2e3-containing nanoparticles in rescuing the rd7 phenotype, animals were examined 2 months after treatment for alterations in their clinical, histological, and morphological phenotypes using indirect ophthalmoscopy, hematoxylin/eosin staining, and electroretinography (ERG), respectively.
While spotting of the fundus was clearly observable when rd7 mice were injected with the blank vector, administration of the Nr2e3 loaded nanoparticles reduced the severity of spotting and provided a partial recovery of the phenotype. Under both photopic and scotopic conditions, improvements in ERG response were observed when comparing the Nr2e3 containing nanoparticles to the blank vector.
We show that nanoparticle delivery of Nr2e3 in the rd7 mice efficiently ameliorated clinical, morphological, and functional defects associated with rd7 retinal degeneration. Following the administration of the Nr2e3 loaded nanoparticles, we observed a partial rescue of the rd7 phenotypes, both by fundus examinations as well as ERG analysis of photoreceptor function. The present study provides promising results toward the development of therapies for human retinal degenerations caused by loss of function of the NR2E3 protein.
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