Regulated control of gene therapies by drug-induced splicing

Alex Mas Monteys (), Amiel A. Hundley, Paul T. Ranum, Luis Tecedor, Amy Muehlmatt, Euyn Lim, Dmitriy Lukashev, Rajeev Sivasankaran and Beverly L. Davidson ()
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Alex Mas Monteys: The Children’s Hospital of Philadelphia
Amiel A. Hundley: The Children’s Hospital of Philadelphia
Paul T. Ranum: The Children’s Hospital of Philadelphia
Luis Tecedor: The Children’s Hospital of Philadelphia
Amy Muehlmatt: The Children’s Hospital of Philadelphia
Euyn Lim: The Children’s Hospital of Philadelphia
Dmitriy Lukashev: Novartis Institutes for BioMedical Research (NIBR)
Rajeev Sivasankaran: Novartis Institutes for BioMedical Research (NIBR)
Beverly L. Davidson: The Children’s Hospital of Philadelphia

Nature, 2021, vol. 596, issue 7871, 291-295

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41586-021-03770-2

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