So far, gene therapies have relied on complex constructs that cannot be finely controlled^1,2. Here we report a universal switch element that enables precise control of gene replacement or gene editing after exposure to a small molecule. The small-molecule inducers are currently 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, which we denote X^on, does not require the co-expression of any regulatory proteins. Using X^on, the translation of the desired elements for controlled gene replacement or gene editing machinery occurs after a single oral dose of the inducer, and the robustness of expression can be controlled by the drug dose, protein stability and redosing. The ability of X^on to provide temporal control of protein expression can be adapted for cell-biology applications and animal studies. Additionally, owing to the oral bioavailability and safety of the drugs used, the X^on switch system provides an unprecedented opportunity to refine and tailor the application of gene therapies in humans.

到目前为止，基因疗法依赖于无法精细控制的复杂结构^1,2。在这里，我们报告了一种通用开关元件，可以在接触小分子后精确控制基因替换或基因编辑。小分子诱导剂目前已用于人类，当给予动物或人类时具有口服生物利用度，并且可以到达外周组织和大脑。此外，我们表示为 X ^on的开关系统不需要任何调节蛋白的共表达。^使用X, 用于受控基因替换或基因编辑机制的所需元素的翻译发生在单次口服剂量的诱导剂后，并且表达的稳健性可以通过药物剂量、蛋白质稳定性和再给药来控制。X ^on提供蛋白质表达的时间控制的能力可以适用于细胞生物学应用和动物研究。此外，由于所用药物的口服生物利用度和安全性，X ^on switch 系统提供了前所未有的机会来改进和定制基因疗法在人类中的应用。