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Genetic control of mammalian T-cell proliferation with synthetic RNA regulatory systems

Chen, Yvonne Y. and Jensen, Michael C. and Smolke, Christina D. (2010) Genetic control of mammalian T-cell proliferation with synthetic RNA regulatory systems. Proceedings of the National Academy of Sciences of the United States of America, 107 (19). pp. 8531-8536. ISSN 0027-8424. http://resolver.caltech.edu/CaltechAUTHORS:20100610-082526664

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Abstract

RNA molecules perform diverse regulatory functions in natural biological systems, and numerous synthetic RNA-based control devices that integrate sensing and gene-regulatory functions have been demonstrated, predominantly in bacteria and yeast. Despite potential advantages of RNA-based genetic control strategies in clinical applications, there has been limited success in extending engineered RNA devices to mammalian gene-expression control and no example of their application to functional response regulation in mammalian systems. Here we describe a synthetic RNA-based regulatory system and its application in advancing cellular therapies by linking rationally designed, drug-responsive, ribozyme-based regulatory devices to growth cytokine targets to control mouse and primary human T-cell proliferation. We further demonstrate the ability of our synthetic controllers to effectively modulate T-cell growth rate in response to drug input in vivo. Our RNA-based regulatory system exhibits unique properties critical for translation to therapeutic applications, including adaptability to diverse ligand inputs and regulatory targets, tunable regulatory stringency, and rapid response to input availability. By providing tight gene-expression control with customizable ligand inputs, RNA-based regulatory systems can greatly improve cellular therapies and advance broad applications in health and medicine.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1073/pnas.1001721107 DOIArticle
http://www.pnas.org/content/107/19/8531PublisherArticle
ORCID:
AuthorORCID
Smolke, Christina D.0000-0002-5449-8495
Additional Information:© 2010 by the National Academy of Sciences. Edited by Mark E. Davis, California Institute of Technology, Pasadena, CA, and approved March 30, 2010 (received for review February 17, 2010). Published online before print April 26, 2010. This Direct Submission article had a prearranged editor. We thank members of the Smolke Lab, Y.A. Chen, and D. Endy, for critical reading of the manuscript; M.N. Win for contributing expertise on ribozyme switch design; and B. Aguilar, C. Bautista, C. Brown, L. Brown, W. Chang, R. Diamond, A. Hamlett, M. Hunter, D. Perez, G. Raval, J. Wagner, W. Wong, and C. Wright for technical assistance. This work was supported by the City of Hope’s National Cancer Institute-Cancer Center Support Grant, the National Science Foundation (fellowship to Y.Y.C.), and the Alfred P. Sloan Foundation (fellowship to C.D.S.). Author contributions: Y.Y.C., M.C.J., and C.D.S. designed research; Y.Y.C. performed research; Y.Y.C., M.C.J., and C.D.S. analyzed data; and Y.Y.C., M.C.J., and C.D.S. wrote the paper.
Funders:
Funding AgencyGrant Number
City of Hope's National Cancer Institute-Cancer Center UNSPECIFIED
NSFUNSPECIFIED
Alfred P. Sloan FoundationUNSPECIFIED
Subject Keywords:nucleic acid therapies; RNA controller; synthetic biology; synthetic riboswitch; immunotherapy
Record Number:CaltechAUTHORS:20100610-082526664
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20100610-082526664
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:18630
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:17 Jun 2010 03:27
Last Modified:25 Jul 2017 19:57

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