Borel Florie, Kay Mark A, Mueller Christian
Gene Therapy Center, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.
Mol Ther. 2014 Apr;22(4):692-701. doi: 10.1038/mt.2013.285. Epub 2013 Dec 19.
RNA interference has become a ubiquitous biological tool, and is being harnessed for therapeutic purposes as well. Therapeutic posttranscriptional gene silencing takes advantage of the endogenous RNAi pathway through delivery of either chemically synthesized siRNAs, or transgenes expressing hairpin-based inhibitory RNAs (e.g., shRNAs and artificial miRNAs). RNAi has expanded the field of viral gene therapy from gene replacement to gene knockdown. Here, we review various noncoding RNAs such as shRNAs, miRNAs, and miRNA decoys which can be utilized for therapeutic applications when expressed from recombinant adeno-associated vectors (AAV), and present examples of their basic design. In addition the basis of exploiting cellular miRNA profiles for detargeting AAV expression from specific cells is described. Finally, an overview of AAV-mediated RNAi preclinical studies is presented, and current RNAi-based clinical trials are reviewed.
RNA干扰已成为一种广泛应用的生物学工具,并且也正被用于治疗目的。治疗性转录后基因沉默通过递送化学合成的小干扰RNA(siRNA)或表达基于发夹结构的抑制性RNA(如短发夹RNA和人工微小RNA)的转基因,利用内源性RNA干扰途径。RNA干扰已将病毒基因治疗领域从基因替代扩展到基因敲低。在此,我们综述了各种非编码RNA,如短发夹RNA、微小RNA和微小RNA诱饵,当它们由重组腺相关病毒(AAV)表达时可用于治疗应用,并给出其基本设计的实例。此外,还描述了利用细胞微小RNA谱使AAV在特定细胞中不表达的原理。最后,概述了AAV介导的RNA干扰临床前研究,并对当前基于RNA干扰的临床试验进行了综述。