Combinatorial RNAi: a winning strategy for the race against evolving targets?
Combinatorial RNAi: a winning strategy for the race against evolving targets?
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DOI：
10.1038/sj.mt.6300116
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发表时间：
2007-05
期刊：
影响因子：
--
通讯作者：
Kay MA
中科院分区：
文献类型：
--
作者：
Grimm D;Kay MA
使用双链RNA抑制基因表达序列的能力(RNA干扰，或RNAi)目前正在给科学和医学带来革命性的变化。许多临床前研究正在评估RNAi作为一种新的治疗方式，用于对抗功能获得常染色体显性疾病、癌症和病毒感染。一个新出现的担忧是，RNAi单一疗法可能最终无法控制那些可以通过突变和/或RNAi抑制而逃脱沉默的病毒。因此，正在开发复杂的策略，旨在通过将RNAi效应器彼此结合或与进一步的基因表达抑制物结合来避免病毒耐药性。一些报告已经验证了这一新的“组合RNAi”(CoRNAi)概念，并通过描述针对单个或多个病毒或细胞靶点的RNAi触发器的共表达来说明其多功能性。其他研究记录了使用额外的基于RNA或蛋白质的消音器成功地传递这些触发因素。此外，已经设计了将RNAi介导的基因抑制与传统的基因替换策略相结合的载体。总的来说，这些努力开辟了令人兴奋的新治疗途径，但也可能增加RNAi技术的内在风险，包括免疫反应、脱离靶向和内源性途径的过饱和。在这里，我们严格审查所有的coRNAi策略，并讨论它们过渡到临床应用的要求。
The ability to use double-stranded RNA to inhibit gene expression sequence-specifically (RNA interference, or RNAi) is currently revolutionizing science and medicine alike. Numerous pre-clinical studies are evaluating RNAi as a novel therapeutic modality in the battle against gain-of-function autosomal dominant diseases, cancer, and viral infections. One emerging concern is that RNAi mono-therapies might ultimately fail to control viruses that can escape silencing by mutation and/or RNAi suppression. Thus, sophisticated strategies are being developed that aim to avert viral resistance by combining RNAi effectors with each other or with further gene expression inhibitors. Several reports already validate this new concept of “combinatorial RNAi” (coRNAi) and illustrate its versatility by describing co-expression of RNAi triggers directed against single or multiple, viral or cellular, targets. Other studies document the successful delivery of these triggers with additional RNA- or protein-based silencers. Moreover, vectors have been engineered to blend RNAi-mediated gene inhibition with conventional gene replacement strategies. Collectively, these efforts open up exciting new therapeutic avenues but could also augment the inherent risks of RNAi technology, including immune responses, off-targeting, and oversaturation of endogenous pathways. Here, we critically review all coRNAi strategies and discuss the requirements for their transition into clinical application.
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影响因子：
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