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<p>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.</p>

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Engineered microRNA scaffolds for potent gene silencing in vivo

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年7月1日

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  • 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

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.