Dykxhoorn Derek M, Lieberman Judy
CBR Institute for Biomedical Research, Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA.
Annu Rev Biomed Eng. 2006;8:377-402. doi: 10.1146/annurev.bioeng.8.061505.095848.
RNA interference (RNAi) is a well-conserved, ubiquitous, endogenous mechanism that uses small noncoding RNAs to silence gene expression. The endogenous small RNAs, called microRNAs, are processed from hairpin precursors and regulate important genes involved in cell death, differentiation, and development. RNAi also protects the genome from invading genetic elements, encoded by transposons and viruses. When small double-stranded RNAs, called small interfering (si)RNAs, are introduced into cells, they bind to the endogenous RNAi machinery to disrupt the expression of mRNAs containing complementary sequences with high specificity. Any disease-causing gene and any cell type or tissue can potentially be targeted. This technique has been rapidly utilized for gene-function analysis and drug-target discovery and validation. Harnessing RNAi also holds great promise for therapy, although introducing siRNAs into cells in vivo remains an important obstacle. Pilot siRNA clinical studies began just three years after the discovery that RNAi works in mammalian cells. This review discusses recent progress and obstacles to using siRNAs as small molecule drugs.
RNA干扰（RNAi）是一种高度保守、普遍存在的内源性机制，它利用小的非编码RNA使基因表达沉默。这种被称为微小RNA（miRNA）的内源性小RNA由发夹状前体加工而成，可调控参与细胞死亡、分化和发育的重要基因。RNAi还能保护基因组免受转座子和病毒编码的入侵遗传元件的影响。当被称为小干扰（si）RNA的小双链RNA被导入细胞时，它们会与内源性RNAi机制结合，以高度特异性地破坏含有互补序列的mRNA的表达。任何致病基因以及任何细胞类型或组织都有可能成为靶点。这项技术已迅速应用于基因功能分析以及药物靶点的发现和验证。尽管将siRNA导入体内细胞仍然是一个重大障碍，但利用RNAi进行治疗也具有巨大潜力。在发现RNAi在哺乳动物细胞中起作用仅三年后，就开始了siRNA的临床试验。这篇综述讨论了将siRNAs用作小分子药物的最新进展和障碍。
