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<p>Adeno-associated viruses (AAVs) are commonly used for gene therapy, but a clinically relevant method to fine-tune AAV expression is lacking, restricting their therapeutic efficacy and safety. Here we develop the drug-elicitable alternative splicing module (DreAM), which is responsive to risdiplam, a Food and Drug Administration-approved alternative splicing modulator. Risdiplam activated DreAM-regulated AAV expression in a dose-dependent manner with a 2,000-fold inducible change, depending on the dose of risdiplam and the organ of interest. With a temporal resolution of 2 days, DreAM could transiently, reversibly and repeatedly activate AAV expression according to the frequency and duration of risdiplam administration. In this proof-of-concept study, we incorporated DreAM into the cardiomyocyte-specific, liver-detargeted AAV9-Tnnt2-miR122TS vector to transiently activate the cardiomyocyte regeneration factor YAP<sup>5SA</sup>. A dedifferentiation–proliferation–redifferentiation cycle was established in adult cardiomyocytes, improving cardiac regeneration after myocardial infarction while limiting animal death, AAV9-Tnnt2 expression in the liver and hepatic tumorigenesis. Therefore, DreAM may enhance the efficacy, safety and scope of gene therapy.</p>

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The drug-elicitable alternative splicing module for tunable vector expression in the heart

  • 期刊论文

  • 发表日期：

    2025年6月13日

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  • Zhan Chen,
  • Luzi Yang,
  • Yueyang Zhang,
  • Jiting Li,
  • Yuhan Yang,
  • Yue Li,
  • Linwei Fan,
  • Wei Chen,
  • Lei Miao,
  • Jin Liu,
  • Gonglie Chen,
  • Ze Wang,
  • Yifei Li,
  • Fei Gao,
  • Jing Zhou,
  • Lemin Zheng,
  • Yan Zhang,
  • Dongyu Zhao,
  • William T. Pu,
  • Ke Yang,
  • Erdan Dong,
  • Yuxuan Guo

摘要

Adeno-associated viruses (AAVs) are commonly used for gene therapy, but a clinically relevant method to fine-tune AAV expression is lacking, restricting their therapeutic efficacy and safety. Here we develop the drug-elicitable alternative splicing module (DreAM), which is responsive to risdiplam, a Food and Drug Administration-approved alternative splicing modulator. Risdiplam activated DreAM-regulated AAV expression in a dose-dependent manner with a 2,000-fold inducible change, depending on the dose of risdiplam and the organ of interest. With a temporal resolution of 2 days, DreAM could transiently, reversibly and repeatedly activate AAV expression according to the frequency and duration of risdiplam administration. In this proof-of-concept study, we incorporated DreAM into the cardiomyocyte-specific, liver-detargeted AAV9-Tnnt2-miR122TS vector to transiently activate the cardiomyocyte regeneration factor YAP5SA. A dedifferentiation–proliferation–redifferentiation cycle was established in adult cardiomyocytes, improving cardiac regeneration after myocardial infarction while limiting animal death, AAV9-Tnnt2 expression in the liver and hepatic tumorigenesis. Therefore, DreAM may enhance the efficacy, safety and scope of gene therapy.