Tunable Gene Control via RNA Splicing with clinically approved small molecule

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.