美国宾夕法尼亚大学Beverly L. Davidson、Alex Mas Monteys等研究人员合作发现，药物诱导的剪接可对基因疗法进行调控。这一研究成果于2021年7月28日在线发表在国际学术期刊《自然》上。
研究人员报道了一种通用的开关元件，能够在接触小分子后精确控制基因替换或基因编辑。这种小分子诱导剂目前在人类中使用，在给动物或人类使用时是口服生物制剂，并能到达外周组织和大脑。此外，研究人员称之为Xon的开关系统不需要任何调节蛋白的共同表达。
通过使用Xon，研究人员表明，基因替换或基因编辑机器所需元件的翻译在单次口服诱导剂后发生，并且表达的稳健性可由药物剂量、蛋白质稳定性和重新给药来控制。Xon提供蛋白质表达的时间控制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，Xon开关系统提供了一个前所未有的机会来完善和调整基因疗法在人类中的应用。
据介绍，到目前为止，基因疗法依赖于复杂的构建体，无法进行精细的控制。
附：英文原文
Title: Regulated control of gene therapies by drug-induced splicing
Author: Monteys, Alex Mas, Hundley, Amiel A., Ranum, Paul T., Tecedor, Luis, Muehlmatt, Amy, Lim, Euyn, Lukashev, Dmitriy, Sivasankaran, Rajeev, Davidson, Beverly L.
Issue&Volume: 2021-07-28
Abstract: So far, gene therapies have relied on complex constructs that cannot be finely controlled1,2. 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 Xon, does not require the co-expression of any regulatory proteins. Using Xon, 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 Xon 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 Xon switch system provides an unprecedented opportunity to refine and tailor the application of gene therapies in humans. A switch system is developed to control the expression of therapeutic genes, involving the administration of a small-molecule drug to induce splicing-mediated control of mRNA translation.
DOI: 10.1038/s41586-021-03770-2
Source: https://www.nature.com/articles/s41586-021-03770-2
Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
官方网址：http://www.nature.com/
投稿链接：http://www.nature.com/authors/submit_manuscript.html
本期文章：《自然》：Online/在线发表
