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M. Ashikari, M. Tokoro, M. Itaya, M. Nozaki, Y. Ogura; Non-Targeted siRNA Suppresses Laser-Induced Choroidal Neovascularization. Invest. Ophthalmol. Vis. Sci. 2009;50(13):1171.
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The previous studies have shown that target- and sequence-independent siRNA suppressed angiogenesis via stimulation of Toll-Like receptor (TLR) - 3 (Kleinman et al., Nature 452:591-7, 2008). The purpose of this study was to determine the target-independent effects of siRNA in the laser-induced CNV model.
Non-targeted siRNAs were 21-nt (nucleotides) siRNA-Luc (Luciferase) or 16-nt siRNA-Luc. Targeted 21-nt siRNA-Vegfa or PBS was used for comparison. CNV was induced by laser injury in C57BL/6J mice, and volumes measured 7 days later by confocal evaluation of Griffonia simplicifolia Isolectin B4 staining of RPE-choroid flatmounts. Various siRNAs or PBS was injected into the vitreous following injury. Leakage from the CNV was also measured by fluorescein angiography 7 days after laser treatment and the lesions were graded based on the fluorescein leakage as follows: 0 (non leaky), 1 (questionable leakage), 2 (leaky) and 3 (pathologically significant leakage) by masked retina specialists.
The mean CNV volume was significantly smaller in the siRNA-Luc (2.6± 8.9 x 105 µm3), siRNA-Vegfa (2.8 ± 5.20x 105 µm3) compared with PBS injected mice (5.8 ± 5.3x 105 µm3); P < 0.0001, P =0.0029, respectively). There was no significant difference between siRNA-Luc injected eyes and siRNA-Vegfa injected eyes (p=0.25). Pathologically significant leakage (grade-3 lesions) developed in most of the PBS injected mice, but in significantly fewer in siRNA-Luc and siRNA-Vegfa injected mice (p<0.001).
Collectively these findings demonstrate that non-target siRNA also can suppress laser-induced CNV as effectively as targeted siRNA, and that siRNAs might induce unanticipated vascular effects.
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