Regulated control of gene therapies by drug induced splicing

RNA Seq datasets from HEK293 cells treated with 25nM LMI070 To date, gene therapies for human application rely on engineered promoters that cannot be finely controlled. Here, we report a universal switch element that allows precise control for gene replacement or gene silencing after exposure to a small molecule. Importantly, these small molecule inducers are in human use, are orally bioavailable when given to animals or humans, and can reach both peripheral tissues and the brain. Moreover, the switch system (Xon) does not require the co-expression of any regulatory proteins. Using Xon, translation of desired elements for controlled gene replacement or editing machinery occurs after a single oral dose, and the robustness of expression can be controlled by drug dose and with repeated drug exposure. The ability of Xon to provide temporal control of protein expression can be adapted to cell biology applications and animal studies. Additionally, due to the oral bioavailability and safety of the drugs employed, the Xon switch provides an unprecedented opportunity to refine gene therapies for more appropriate human application. Data from 4 LMI070 (25nM) treated and 4 DMSO treated HEK293 cell groups were obtained after sequencing across two lanes run on an Illumina Hi-Seq 4000.