In vivo activity of nuclease-resistant siRNAs
In vivo activity of nuclease-resistant siRNAs
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DOI：
10.1261/rna.5239604
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发表时间：
2004-05-01
期刊：
影响因子：
4.5
通讯作者：
Sullenger, BA
中科院分区：
文献类型：
--
作者：
Layzer, JM;McCaffrey, AP;Sullenger, BA
化学修饰已被纳入短干扰RNA（siRNA），而不会降低其抑制体外生长的哺乳动物细胞中基因表达的能力。在本研究中，我们开始评估2 '-修饰的siRNA在哺乳动物中的潜在效用。我们证明了用2 ′-氟（2 ′-F）嘧啶修饰的siRNA在细胞培养中是有功能的，并且与含有2 ′-OH的siRNA相比，在人血浆中具有大大增加的稳定性和延长的半衰期。此外，我们表明含2 '-F的siRNA在小鼠中是有功能的，并且可以抑制靶基因的体内表达。然而，即使修饰的siRNA对血浆中核酸酶降解的抗性大大增加，但这种稳定性的增加并没有转化为尾静脉注射后小鼠中靶基因减少的增强或延长的抑制活性。因此，该研究表明，2 '-F修饰的siRNA在体内是有功能的，但它们在动物中不一定比未修饰的siRNA更有效。
Chemical modifications have been incorporated into short interfering RNAs (siRNAs) without reducing their ability to inhibit gene expression in mammalian cells grown in vitro. In this study, we begin to assess the potential utility of 2'-modified siRNAs in mammals. We demonstrate that siRNA modified with 2'-flouro (2'-F) pyrimidines are functional in cell culture and have a greatly increased stability and a prolonged half-life in human plasma as compared to 2'-OH containing siRNAs. Moreover, we show that the 2'-F containing siRNAs are functional in mice and can inhibit the expression of a target gene in vivo. However, even though the modified siRNAs have greatly increased resistance to nuclease degradation in plasma, this increase in stability did not translate into enhanced or prolonged inhibitory activity of target gene reduction in mice following tail vein injection. Thus, this study shows that 2'-F modified siRNAs are functional in vivo, but that they are not necessarily more potent than unmodified siRNAs in animals.