Editors' ChoiceSynthetic Biology

Engineered cells to treat hyperthyroidism

Sci. Signal.  09 Feb 2016:
Vol. 9, Issue 414, pp. ec25
DOI: 10.1126/scisignal.aaf4256

Graves’ disease is an autoimmune disease characterized by severe metabolic abnormalities due to excess thyroid hormones in the circulation (hyperthyroidism). Autoantibodies generated in this condition bind to thyroid-stimulating hormone receptor (TSHR) on the thyroid gland and trigger excess release of thyroid hormones, triiodothyronine (T3) and thyroxine (T4). Thyroid receptors (TRα and TRβ) present in peripheral and central nervous tissues are nuclear hormone receptors that bind to secreted thyroid hormones and activate or repress genes involved in metabolism. Saxena et al. designed and evaluated a synthetic cellular circuit that monitored the amount of thyroid hormones and secreted an engineered protein that binds to and inhibits TSHR. The synthetic circuit comprised expression of plasmids encoding the following, all of which were controlled by the Gal4 promoter sequence: a synthetic thyroid hormone–sensing receptor (TSR) composed of TRα fused to the DNA-binding domain of yeast Gal4, which bound to the promoter sequences of the circuit genes; a human placental secreted alkaline phosphatase (SEAP); an enzyme that converts T4 to T3; and a high-affinity thyroid-stimulating hormone (TSH) antagonist (TSHantag) that binds to TSHR and competitively inhibits binding of TSH or the autoantibodies. TSR bound the Gal4 sequence in the promoters of all four of the genes in the circuit. In the absence of T3, TSR recruited corepressors, thereby suppressing the circuit. In the presence of T3, TSR recruited coactivators, thereby activating the circuit and triggering the expression and secretion of SEAP and TSHantag. After testing several cell types, transfection efficiencies and SEAP and TSHantag production and secretion were the highest in CHO-K1 cells. Bead-encapsulated CHO-K1 cells with the engineered synthetic circuit, implanted intraperitoneally in mice that are a model for Graves’ disease, reduced the amount of circulating T4 when compared with control mice implanted with microencapsulated CHO-K1 cells without the TSHantag plasmid in the synthetic circuit. Thus, a self-monitoring synthetic cellular signaling circuit could help maintain metabolic homeostasis without external interventions, such as drugs or surgery, in patients with hyperthyroidism.

P. Saxena, G. Charpin-El Hamri, M. Folcher, H. Zulewski, M. Fussenegger, Synthetic gene network restoring endogenous pituitary–thyroid feedback control in experimental Graves’ disease. Proc. Natl. Acad. Sci. USA. 113, 1244–1249 (2016). [PubMed]

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