title: Implantable synthetic cytokine converter cells with AND-gate logic treat experimental psoriasis.
abstract: Psoriasis is a chronic inflammatory skin disease characterized by a relapsing-remitting disease course and correlated with increased expression of proinflammatory cytokines, such as tumor necrosis factor (TNF) and interleukin 22 (IL22). Psoriasis is hard to treat because of the unpredictable and asymptomatic flare-up, which limits handling of skin lesions to symptomatic treatment. Synthetic biology-based gene circuits are uniquely suited for the treatment of diseases with complex dynamics, such as psoriasis, because they can autonomously couple the detection of disease biomarkers with the production of therapeutic proteins. We designed a mammalian cell synthetic cytokine converter that quantifies psoriasis-associated TNF and IL22 levels using serially linked receptor-based synthetic signaling cascades, processes the levels of these proinflammatory cytokines with AND-gate logic, and triggers the corresponding expression of therapeutic levels of the anti-inflammatory/psoriatic cytokines IL4 and IL10, which have been shown to be immunomodulatory in patients. Implants of microencapsulated cytokine converter transgenic designer cells were insensitive to simulated bacterial and viral infections as well as psoriatic-unrelated inflammation. The designer cells specifically prevented the onset of psoriatic flares, stopped acute psoriasis, improved psoriatic skin lesions and restored normal skin-tissue morphology in mice. The antipsoriatic designer cells were equally responsive to blood samples from psoriasis patients, suggesting that the synthetic cytokine converter captures the clinically relevant cytokine range. Implanted designer cells that dynamically interface with the patient's metabolism by detecting specific disease metabolites or biomarkers, processing their blood levels with synthetic circuits in real time, and coordinating immediate production and systemic delivery of protein therapeutics may advance personalized gene- and cell-based therapies.
authors.affiliation: Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, CH-4058 Basel, Switzerland.
authors.forename: Lina
authors.initials: L
authors.lastname: Schukur
authors.affiliation: Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, CH-4058 Basel, Switzerland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Geering
authors.affiliation: Département Génie Biologique, Institut Universitaire de Technologie, F-69622 Villeurbanne Cedex, France.
authors.forename: Ghislaine
authors.initials: G
authors.lastname: Charpin-El Hamri
authors.affiliation: Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, CH-4058 Basel, Switzerland. Faculty of Science, University of Basel, Mattenstrasse 26, CH-4058 Basel, Switzerland. fussenegger@bsse.ethz.ch.
authors.forename: Martin
authors.initials: M
authors.lastname: Fussenegger
mesh_terms: D000634:Aminoquinolines; D000818:Animals; D016466:CHO Cells; D017690:Cell Transplantation / Q000379:methods*; D003412:Cricetulus; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation; D005818:Genetic Engineering / Q000379:methods*; D015316:Genetic Therapy / Q000379:methods*; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D000077271:Imiquimod; D018836:Inflammation Mediators / Q000378:metabolism; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D015847:Interleukin-4 / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D007378:Interleukins / Q000235:genetics / Q000378:metabolism; D008128:Logic; D008810:Mice, Inbred C57BL; D011565:Psoriasis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D015203:Reproducibility of Results; D015398:Signal Transduction; D012867:Skin / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D000097043:Interleukin-22
chemical_list: D000634:Aminoquinolines; D000077271:Imiquimod; D018836:Inflammation Mediators; D016753:Interleukin-10; D015847:Interleukin-4; D007378:Interleukins; D014409:Tumor Necrosis Factor-alpha; D000097043:Interleukin-22; C508609:IL10 protein, human; C508598:IL4 protein, human