title: A Synthetic Mammalian Therapeutic Gene Circuit for Sensing and Suppressing Inflammation.
abstract: Inflammation, which is a highly regulated host response against danger signals, may be harmful if it is excessive and deregulated. Ideally, anti-inflammatory therapy should autonomously commence as soon as possible after the onset of inflammation, should be controllable by a physician, and should not systemically block beneficial immune response in the long term. We describe a genetically encoded anti-inflammatory mammalian cell device based on a modular engineered genetic circuit comprising a sensor, an amplifier, a "thresholder" to restrict activation of a positive-feedback loop, a combination of advanced clinically used biopharmaceutical proteins, and orthogonal regulatory elements that linked modules into the functional device. This genetic circuit was autonomously activated by inflammatory signals, including endogenous cecal ligation and puncture (CLP)-induced inflammation in mice and serum from a systemic juvenile idiopathic arthritis (sIJA) patient, and could be reset externally by a chemical signal. The microencapsulated anti-inflammatory device significantly reduced the pathology in dextran sodium sulfate (DSS)-induced acute murine colitis, demonstrating a synthetic immunological approach for autonomous anti-inflammatory therapy.
authors.affiliation: Department of Synthetic Biology and Immunology, National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia.
authors.forename: Anže
authors.initials: A
authors.lastname: Smole
authors.affiliation: Department of Synthetic Biology and Immunology, National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia.
authors.forename: Duško
authors.initials: D
authors.lastname: Lainšček
authors.affiliation: Department of Synthetic Biology and Immunology, National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia; Faculty of Chemistry and Chemical Technology, University of Ljubljana, 1000 Ljubljana, Slovenia.
authors.forename: Urban
authors.initials: U
authors.lastname: Bezeljak
authors.affiliation: Department of Synthetic Biology and Immunology, National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia; EN-FIST Centre of Excellence, 1000 Ljubljana, Slovenia; Biotechnical Faculty, University of Ljubljana, 1000 Ljubljana, Slovenia.
authors.forename: Simon
authors.initials: S
authors.lastname: Horvat
authors.affiliation: Department of Synthetic Biology and Immunology, National Institute of Chemistry, Hajdrihova 19, 1000 Ljubljana, Slovenia; EN-FIST Centre of Excellence, 1000 Ljubljana, Slovenia. Electronic address: roman.jerala@ki.si.
authors.forename: Roman
authors.initials: R
authors.lastname: Jerala
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents; D002460:Cell Line; D003092:Colitis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015195:Drug Design; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D015202:Protein Engineering; D015398:Signal Transduction; D058615:Synthetic Biology
chemical_list: D000893:Anti-Inflammatory Agents; D016207:Cytokines; D018836:Inflammation Mediators
keywords: anti-inflammatory therapy; gene circuit; mammalian cell engineering; synthetic biology