In Vivo Delivery of Cytoplasmic RNA Virus-derived miRNAs
In Vivo Delivery of Cytoplasmic RNA Virus-derived miRNAs
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DOI：
10.1038/mt.2011.244
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发表时间：
2012-02-01
影响因子：
12.4
通讯作者：
tenOever, Benjamin R.
中科院分区：
文献类型：
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作者：
Langlois, Ryan A.;Shapiro, Jillian S.;tenOever, Benjamin R.
微小RNA（miRNA）的发现揭示了细胞用于维持最佳蛋白质水平的转录后控制水平。这一过程代表了目前受体内递送限制的治疗剂的有吸引力的策略。在这里，我们描述了一种能够产生功能性miRNA的负极性单链细胞质病毒的产生。细胞质RNA病毒衍生的miRNA在体外积累到高水平，产生大量的miRNA星星链，与RNA诱导的沉默复合物（RISC）相关，并以序列特异性方式赋予转录后基因沉默。此外，我们证明这些载体可以将miRNA递送到广泛的组织中，并维持能够在体内实现可测量的生理靶点敲低的长期表达。总之，这些结果验证了细胞质衍生的miRNA的非规范加工，并为小RNA递送提供了一个新的平台。
The discovery of microRNAs (miRNAs) revealed an unappreciated level of post-transcriptional control used by the cell to maintain optimal protein levels. This process has represented an attractive strategy for therapeutics that is currently limited by in vivo delivery constraints. Here, we describe the generation of a single-stranded, cytoplasmic virus of negative polarity capable of producing functional miRNAs. Cytoplasmic RNA virus-derived miRNAs accumulated to high levels in vitro, generated significant amounts of miRNA star strand, associated with the RNA-induced silencing complex (RISC), and conferred post transcriptional gene silencing in a sequence-specific manner. Furthermore, we demonstrate that these vectors could deliver miRNAs to a wide range of tissues, and sustain prolonged expression capable of achieving measurable knockdown of physiological targets in vivo. Taken together, these results validate noncanonical processing of cytoplasmic-derived miRNAs and provide a novel platform for small RNA delivery.