Self-sufficient control of urate homeostasis in mice by a synthetic circuit

Kemmer, Christian; Gitzinger, Marc; Daoud-El Baba, Marie; Djonov, Valentin; Stelling, Jörg; Fussenegger, Martin (2010). Self-sufficient control of urate homeostasis in mice by a synthetic circuit. Nature biotechnology, 28(4), pp. 355-60. New York, N.Y.: Nature America 10.1038/nbt.1617

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Synthetic biology has shown that the metabolic behavior of mammalian cells can be altered by genetic devices such as epigenetic and hysteretic switches, timers and oscillators, biocomputers, hormone systems and heterologous metabolic shunts. To explore the potential of such devices for therapeutic strategies, we designed a synthetic mammalian circuit to maintain uric acid homeostasis in the bloodstream, disturbance of which is associated with tumor lysis syndrome and gout. This synthetic device consists of a modified Deinococcus radiodurans-derived protein that senses uric acids levels and triggers dose-dependent derepression of a secretion-engineered Aspergillus flavus urate oxidase that eliminates uric acid. In urate oxidase-deficient mice, which develop acute hyperuricemia, the synthetic circuit decreased blood urate concentration to stable sub-pathologic levels in a dose-dependent manner and reduced uric acid crystal deposits in the kidney. Synthetic gene-network devices providing self-sufficient control of pathologic metabolites represent molecular prostheses, which may foster advances in future gene- and cell-based therapies.

Item Type:

Journal Article (Further Contribution)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Anatomy

UniBE Contributor:

Djonov, Valentin

ISSN:

1087-0156

Publisher:

Nature America

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:11

Last Modified:

17 Mar 2015 19:13

Publisher DOI:

10.1038/nbt.1617

PubMed ID:

20351688

Web of Science ID:

000276462400023

URI:

https://boris.unibe.ch/id/eprint/2021 (FactScience: 204169)

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