RNA interference: from gene silencing to gene-specific therapeutics

被引:290
作者
Leung, RKM [1 ]
Whittaker, PA [1 ]
机构
[1] Novartis Inst Biomed Res, Resp Dis Area, Horsham RH12 5AB, W Sussex, England
关键词
RNAi; siRNA; shRNA; disease; validation; therapy;
D O I
10.1016/j.pharmthera.2005.03.004
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
In the past 4 years, RNA interference (RNAi) has become widely used as all experimental tool to analyse the function of mammalian genes, both in vitro and in vivo. By harnessing an evolutionary conserved endogenous biological pathway, first identified in plants and lower organisms, double-stranded RNA (dsRNA) reagents are used to bind to and promote the degradation of target RNAs, resulting in knockdown of the expression of specific genes. RNAi can be induced in mammalian cells by the introduction of synthetic double-stranded small interfering RNAs (siRNAs) 21-23 base pairs (bp) in length or by plasmid and viral vector systems that express double-stranded short hairpin RNAs (shRNAs) that are subsequently processed to siRNAs by the cellular machinery. RNAi has been widely used in mammalian cells to define the functional roles of individual genes, particularly in disease. In addition, siRNA and shRNA libraries have been developed to allow the systematic analysis of genes required for disease processes such as cancer using high throughput RNAi screens. RNAi has been used for the knockdown of gene expression in experimental animals, with the development of shRNA systems that allow tissue-specific and inducible knockdown of genes promising to provide a quicker and cheaper way to generate transgenic animals than conventional approaches. Finally, because of the ability of RNAi to silence disease-associated genes in tissue culture and animal models, the development of RNAi-based reagents for clinical applications is gathering pace, as technological enhancements that improve siRNA stability and delivery in vivo, while minimising off-target and nonspecific effects, are developed. (c) 2005 Elsevier Inc. All rights reserved.
引用
收藏
页码:222 / 239
页数:18
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