Controlling transgene expression in subcutaneous implants using a skin lotion containing the apple metabolite phloretin
Language: 
English
Abstract: 

Adjustable control of therapeutic transgenes in engineered cell implants after transdermal and topical delivery of nontoxic trigger molecules would increase convenience, patient compliance, and elimination of hepatic first-pass effect in future therapies. Pseudomonas putida DOT-T1E has evolved the flavonoid-triggered TtgR operon, which controls expression of a multisubstrate-specific efflux pump (TtgABC) to resist plant-derived defense metabolites in its rhizosphere habitat. Taking advantage of the TtgR operon, we have engineered a hybrid P. putida-mammalian genetic unit responsive to phloretin. This flavonoid is contained in apples, and, as such, or as dietary supplement, regularly consumed by humans. The engineered mammalian phloretin-adjustable control element (PEACE) enabled adjustable and reversible transgene expression in different mammalian cell lines and primary cells. Due to the short half-life of phloretin in culture, PEACE could also be used to program expression of difficult-to-produce protein therapeutics during standard bioreactor operation. When formulated in skin lotions and applied to the skin of mice harboring transgenic cell implants, phloretin was able to fine-tune target genes and adjust heterologous protein levels in the bloodstream of treated mice. PEACE-controlled target gene expression could foster advances in biopharmaceutical manufacturing as well as gene- and cell-based therapies.

Author(s): 
Gitzinger, Marc
Kemmer, Christian
El-Baba, Marie Daoud
Weber, Wilfried
Fussenegger, Martin
Item Type: 
Journal Article
Publication Title: 
Proceedings of the National Academy of Sciences of the United States of America
Journal Abbreviation: 
Proc. Natl. Acad. Sci. U.S.A.
Publication Date: 
Jun 30, 2009
Publication Year: 
2009
Pages: 
10638-10643
Volume: 
106
Issue: 
26
ISSN: 
1091-6490
DOI: 
10.1073/pnas.0901501106
Library Catalog: 
NCBI Published Medical (?)
Extra: 
PMID: 19549857 PMCID: PMC2700147

Turabian/Chicago Citation

Marc Gitzinger, Christian Kemmer, Marie Daoud El-Baba, Wilfried Weber and Martin Fussenegger. Jun 30, 2009. "Controlling transgene expression in subcutaneous implants using a skin lotion containing the apple metabolite phloretin." Proceedings of the National Academy of Sciences of the United States of America 106: 26: 10638-10643. 10.1073/pnas.0901501106.

Wikipedia Citation

<ref> {{Cite journal | doi = 10.1073/pnas.0901501106 | issn = 1091-6490 | volume = 106 | pages = 10638-10643 | last = Gitzinger | first = Marc | coauthors = Kemmer, Christian, El-Baba, Marie Daoud, Weber, Wilfried, Fussenegger, Martin | title = Controlling transgene expression in subcutaneous implants using a skin lotion containing the apple metabolite phloretin | journal = Proceedings of the National Academy of Sciences of the United States of America | date = Jun 30, 2009 | pmid = | pmc = }} </ref>