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Regulated control of gene therapies by drug-induced splicing
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Journal Article
Regulated control of gene therapies by drug-induced splicing
2021
Overview
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.
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.
Publisher
Nature Publishing Group UK,Nature Publishing Group
Subject
/ 38
/ 42
/ 42/44
/ 631/337
/ 631/61
/ 82
/ 82/80
/ Alternative Splicing - drug effects
/ Animals
/ CRISPR-Associated Protein 9 - metabolism
/ Datasets
/ Drug Delivery Systems - methods
/ Erythropoietin - biosynthesis
/ Female
/ Frontotemporal Dementia - metabolism
/ Humanities and Social Sciences
/ Humans
/ Kinases
/ Male
/ Mice
/ Muscular Atrophy, Spinal - metabolism
/ Neuronal Ceroid-Lipofuscinoses - metabolism
/ Protein Biosynthesis - drug effects
/ Proteins
/ Science
/ Splicing
