Tunable gene control via RNA splicing with a clinically approved small molecule
Summary
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. © 2026. The Author(s).
| Authors | Mendel M, Schwarz D, Sun T, Tan S, Franceschetti A, Majcher D, Lang S, Venetz D, Ratni H, Jagasia R, Ebeling M, Roudnicky F, Schukur L |
|---|---|
| Journal | Nature communications |
| Publication Date | 2026 May 30;17(1) |
| PubMed | 42218123 |
| PubMed Central | PMC13392007 |
| DOI | 10.1038/s41467-026-73673-1 |