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<p>Precise transgene regulation is crucial for safe and effective gene and cell therapies. Current inducible systems often rely on immunogenic exogenous proteins or non-clinically approved inducers, hindering clinical translation. Here we present RisdiON, a compact inducible system controlled by risdiplam, a clinically approved oral drug that acts via splicing modulation. RisdiON utilizes risdiplam-responsive sequences for precise transgene control via endogenous splicing machinery, bypassing exogenous protein regulators, while its split-ATG architecture ensures the expression of native, tag-free proteins. This approach provides robust, dose-dependent induction with minimal leakiness. We demonstrate that RisdiON controls various transgenes in immortalized cell lines and hiPSCs, enables inducible CAR expression in primary T cells, and regulates Cas9 for precise gene editing. Additionally, we achieve reversible transgene expression in vivo using adeno-associated virus (AAV) delivery. The platform is modular and functional across diverse promoters, offering a safe, titratable, and reversible tool when coupled with an orally bioavailable drug to advance next-generation therapies.</p>

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Tunable gene control via RNA splicing with a clinically approved small molecule

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年5月30日

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  • Mateusz Mendel,
  • Dominic Schwarz,
  • Tao Sun,
  • Sophia Tan,
  • Asia Franceschetti,
  • Daria Majcher,
  • Simone Lang,
  • Dario Venetz,
  • Hasane Ratni,
  • Ravi Jagasia,
  • Martin Ebeling,
  • Filip Roudnicky,
  • Lina Schukur

摘要

Precise transgene regulation is crucial for safe and effective gene and cell therapies. Current inducible systems often rely on immunogenic exogenous proteins or non-clinically approved inducers, hindering clinical translation. Here we present RisdiON, a compact inducible system controlled by risdiplam, a clinically approved oral drug that acts via splicing modulation. RisdiON utilizes risdiplam-responsive sequences for precise transgene control via endogenous splicing machinery, bypassing exogenous protein regulators, while its split-ATG architecture ensures the expression of native, tag-free proteins. This approach provides robust, dose-dependent induction with minimal leakiness. We demonstrate that RisdiON controls various transgenes in immortalized cell lines and hiPSCs, enables inducible CAR expression in primary T cells, and regulates Cas9 for precise gene editing. Additionally, we achieve reversible transgene expression in vivo using adeno-associated virus (AAV) delivery. The platform is modular and functional across diverse promoters, offering a safe, titratable, and reversible tool when coupled with an orally bioavailable drug to advance next-generation therapies.