Engineered microRNA scaffolds for potent gene silencing in vivo

作者: Giuseppe Militello, Alyssa Greig, Chongfeng Bi, Ana Vasileva, Maria I. Zavodszky, Shih-Ching Lo, Edward Guilmette, Pete Clarner, Bin Liu, Guruharsha Bhat, Junghae Suh, Lukas Dow, Johannes Zuber, Christof Fellmann & Prem K. Premsrirut
杂志: Scientific Reports
Doi: https://www.doi.org/10.1038/s41598-025-07061-y
出版日期: 2025-7-1

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摘要

RNA interference (RNAi) is emerging as a powerful strategy for therapeutic targeting of “undruggable” targets. However, efficacy of currently used siRNA-based therapies is often hindered by transient effects and limited modeling possibilities. Artificial microRNAs (amiRNAs or miRNA scaffolds) present a durable and precise approach to gene silencing, opening new avenues for developing long lasting targeted therapies. In this study, we engineered highly expressed primary miRNAs (pri-miRNAs) with sequence determinants known to enhance processing efficacy and precision. The resulting amiRNAs were extensively tested both in vitro and in vivo and proved to efficiently silence a target gene when virally delivered via adeno-associated virus (AAV) into mice brains. This study provides a set of novel amiRNAs with potential therapeutic application as well as a pipeline to generate and validate novel amiRNAs from endogenous pri-miRNAs.

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