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M. Nozaki, R. J. C. Albuquerque, M. E. Kleinman, S. De Falco, T. A. Wilgus, L. A. DiPietro, J. Ambati; Non-Targeted siRNA Suppress Angiogenesis in the Cornea, Dermis and Hind Limb. Invest. Ophthalmol. Vis. Sci. 2008;49(13):525. doi: https://doi.org/.
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© ARVO (1962-2015); The Authors (2016-present)
Small interfering RNAs (siRNAs) are presumed to specifically knockdown target mRNAs in a sequence-dependent manner. Clinical trials of siRNAs targeting pro-angiogenic VEGF and VEGFR-1 are ongoing. Yet, the contribution of specific RNA interference of siRNAs has not been determined in vivo. We have reported that non-targeted siRNA suppresses laser-induced choroidal neovascularization to the same extent as targeted siRNA (Kleinman et al. ARVO, 2008). This study sought to determine the global potential of non-targeted siRNA to inhibit angiogenesis in different organ systems.
Balb/C and C57Bl/6 mice were studied. Non-targeted siRNAs were 21-nt (nucleotides) siRNA-Luc (firefly luciferase) or 7-nt siRNA-Luc. Targeted 21-nt siRNA-Vegfa, siRNA buffer or PBS were used for comparison. The mouse models of suture-induced corneal neovascularization, hind limb ischemia (HLI) and dermal wounding neovascularization (WDV) were studied. The extent of the angiogenic response was assessed by immunochemical techniques.
21-nt siRNA-Luc and 21-nt siRNA-Vegfa abolished suture-induced corneal neovascularization (NV), whereas 7-nt siRNA-Luc or the siRNA buffer alone did not. In the HLI model, both 21-nt siRNAs showed significantly reduction in angiogenesis by 30% compare to PBS or 7-nt siRNA (p<0.01). Similarly, in the WDV model, both 21-nt siRNAs decreased the percent dermal CD31 positive area by approximately 50% compared to 7-nt siRNA or PBS alone (p<0.01).
Our data demonstrated that 21-nt siRNAs, targeted and non-targeted, are capable of equally suppressing angiogenesis in the cornea, dermis and hind limb. These findings suggest that the in vivo anti-angiogenic effects of siRNAs are global, length-dependent and sequence non-specific.
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