Therapeutic application of RNA interference to suppress hepatitis C virus replication

小干扰RNA （sirna）通过RNA干扰有效抑制基因表达。在这里，我们报道了使用HCV复制子系统，通过合成和载体衍生的sirna有效抑制丙型肝炎病毒（HCV）复制以及病毒蛋白合成。sirna被设计用于HCV基因组的5' -未翻译区（5' -UTR），该区域具有整个病毒多蛋白翻译的内部核糖体进入位点。此外，5' -UTR在整个基因组中是最保守的，使其成为siRNA的理想靶标。重要的是，我们已经在5' -UTRR内确定了一个非常有效的位点，在低至2.5 nM的siRNA浓度下，对HCV复制的抑制达到了^ ~ 80%。此外，基于dna的表达siRNA的HCV载体也是有效的，这可能允许在体内使用病毒载体将RNAi基因传递到肝细胞中。综上所述，我们的研究结果支持利用基于sirna的基因疗法抑制HCV复制的可行性，这可能在丙型肝炎的治疗中证明是有价值的。

Small interfering RNAs (siRNAs) efficiently inhibit gene expression by RNA interference. Here, we report efficient inhibition, by both synthetic and vector-derived siRNAs, of hepatitis C virus (HCV) replication, as well as viral protein synthesis, using an HCV replicon system. The siRNAs were designed to target the 5' -untranslated region (5' -UTR) of the HCV genome, which has an internal ribosomal entry site for translation of the entire viral polyprotein. Moreover, 5' -UTR is the most conserved throughout the genome, making it an ideal target for siRNA. Importantly, we have identified a very effective site within 5' -UTRR, where ^〜80% suppression of HCV replication was achieved with concentrations of siRNA as low as 2.5 nM. Furthermore, DNA-based vectors expressing siRNA against HCV also were effective, which might allow efficient gene delivery of RNAi into hepatocytes in vivo using virus vectors. Taken together, our results support the feasibility of utilizing siRNA-based gene therapy to inhibit HCV replication, which may prove valuable in the therapy of hepatitis C.