title: Synthetic gene network restoring endogenous pituitary-thyroid feedback control in experimental Graves' disease.
abstract: Graves' disease is an autoimmune disorder that causes hyperthyroidism because of autoantibodies that bind to the thyroid-stimulating hormone receptor (TSHR) on the thyroid gland, triggering thyroid hormone release. The physiological control of thyroid hormone homeostasis by the feedback loops involving the hypothalamus-pituitary-thyroid axis is disrupted by these stimulating autoantibodies. To reset the endogenous thyrotrophic feedback control, we designed a synthetic mammalian gene circuit that maintains thyroid hormone homeostasis by monitoring thyroid hormone levels and coordinating the expression of a thyroid-stimulating hormone receptor antagonist (TSHAntag), which competitively inhibits the binding of thyroid-stimulating hormone or the human autoantibody to TSHR. This synthetic control device consists of a synthetic thyroid-sensing receptor (TSR), a yeast Gal4 protein/human thyroid receptor-α fusion, which reversibly triggers expression of the TSHAntag gene from TSR-dependent promoters. In hyperthyroid mice, this synthetic circuit sensed pathological thyroid hormone levels and restored the thyrotrophic feedback control of the hypothalamus-pituitary-thyroid axis to euthyroid hormone levels. Therapeutic plug and play gene circuits that restore physiological feedback control in metabolic disorders foster advanced gene- and cell-based therapies.
authors.affiliation: Department of Biosystems Science and Engineering, Eidgenössiche Technische Hochschule Zurich, CH-4058 Basel, Switzerland;
authors.forename: Pratik
authors.initials: P
authors.lastname: Saxena
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, Eidgenössiche Technische Hochschule Zurich, CH-4058 Basel, Switzerland;
authors.forename: Marc
authors.initials: M
authors.lastname: Folcher
authors.affiliation: Department of Biosystems Science and Engineering, Eidgenössiche Technische Hochschule Zurich, CH-4058 Basel, Switzerland; Division of Endocrinology, Diabetes and Metabolism, University Hospital Basel, CH-4031 Basel, Switzerland;
authors.forename: Henryk
authors.initials: H
authors.lastname: Zulewski
authors.affiliation: Department of Biosystems Science and Engineering, Eidgenössiche Technische Hochschule Zurich, CH-4058 Basel, Switzerland; Faculty of Science, University of Basel, CH-4058 Basel, Switzerland martin.fussenegger@bsse.ethz.ch.
authors.forename: Martin
authors.initials: M
authors.lastname: Fussenegger
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005246:Feedback; D053263:Gene Regulatory Networks; D005813:Genes, Synthetic; D006111:Graves Disease / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D051379:Mice; D010902:Pituitary Gland / Q000503:physiopathology*; D013961:Thyroid Gland / Q000503:physiopathology*; D013963:Thyroid Hormones / Q000097:blood
chemical_list: D013963:Thyroid Hormones
keywords: cell engineering; designer cells; gene switch; prosthetic networks; synthetic biology