Regulated control of gene therapies by drug-induced splicing

被引:79
作者
Monteys, Alex Mas [1 ,2 ]
Hundley, Amiel A. [1 ]
Ranum, Paul T. [1 ]
Tecedor, Luis [1 ]
Muehlmatt, Amy [1 ]
Lim, Euyn [1 ]
Lukashev, Dmitriy [3 ]
Sivasankaran, Rajeev [3 ]
Davidson, Beverly L. [1 ,2 ]
机构
[1] Childrens Hosp Philadelphia, Raymond G Perelman Ctr Cellular & Mol Therapeut, Philadelphia, PA 19104 USA
[2] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA
[3] Novartis Inst BioMed Res NIBR, Neurosci Dis Area, Cambridge, MA USA
基金
美国国家卫生研究院;
关键词
IN-VIVO; TRANSGENE EXPRESSION; ENDOGENOUS MICRORNA; VISUALIZATION; TRANSLATION;
D O I
10.1038/s41586-021-03770-2
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:291 / +
页数:23
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