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Veronica Ruz, Covadonga Paneda, Tamara Martinez, Susana Monteiro, Amor Guerra, Victoria Gonzalez, Ana Isabel Jimenez; Topical administration of siRNA targeting NRARP as a new treatment for choroidal neovascularization. Invest. Ophthalmol. Vis. Sci. 2018;59(9):2634.
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To assess the role of NRARP (NOTCH Regulated Ankyrin Repeat Protein) in choroidal neovascularization and to obtain a proof-of concept study to demonstrate that topical administration of a siRNA targeting NRARP is an attractive therapeutic avenue for AMD (Age-related macular degeneration)
A battery of siRNAs designed to silence NRARP was evaluated in vitro and the most efficacious product was selected for further development for the treatment of AMD. In vivo efficacy of a chemically stabilized siRNA version was studied in a model of laser-induced choroidal neovascularization in rats. We also assessed the ability of the compound to reach the retina when administered topically to rabbits
SYL136001v10 was selected as the most potent of the sequences studied, causing a maximal reduction of NRARP mRNA levels of 80% in human cells and 70% in rat cells. This effect was observed without reduction of cell viability. SYL136001v10 was administered as a single dose in eye drops to rabbits and analysis of the tissues collected showed that the intact compound was present in retina. Repeated administrations of the compound to rats with laser induced CNV-lesions showed a statistically significant reduction in the size and leakage of lesions compared to vehicle instillation; this therapeutic effect was equivalent to the reduction observed in response to an IVT-injection of an anti-VEGF antibody. The reduction in laser-induced lesions correlated with a reduction in NRARP gene expression in retina and choroid
A siRNA that efficiently down-regulates a new target for AMD named NRARP has been identified. The results of the efficacy study in the CNV-animal model and the biodistribution in rabbits indicate that topical application of siRNA targeting NRARP is a potential new avenue for treating angiogenic retinal diseases
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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