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Tunable Gene Control via RNA Splicing with clinically approved small molecule

ABSTRACT: 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. We developed 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. RisdiON demonstrated broad utility, controlling various transgenes in immortalized cell lines and hiPSCs, enabling inducible CAR expression in primary T cells, and regulating Cas9 for precise gene editing. Additionally, adeno-associated virus (AAV)-delivered RisdiON achieved reversible transgene expression in vivo. 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE320370 | GEO | 2026/04/30

REPOSITORIES: GEO

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