Research ArticleCELL ENGINEERING

A green tea–triggered genetic control system for treating diabetes in mice and monkeys

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Science Translational Medicine  23 Oct 2019:
Vol. 11, Issue 515, eaav8826
DOI: 10.1126/scitranslmed.aav8826

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Tea for type 1 and type 2 diabetes

Cell therapy is a promising approach for diabetes. Yin et al. developed an elegant control system by engineering cells to respond to protocatechuic acid, a metabolite in green tea. Orally ingested protocatechuic acid regulated blood glucose by triggering secretion of insulin or a short variant of human glucagon-like peptide 1 from implanted engineered cells in mouse and nonhuman primate models of type 1 and type 2 diabetes. This study demonstrates the versatility of synthetic biology for developing remotely controlled cell-based therapies for diabetes.

Abstract

Cell-based therapies are recognized as the next frontier in medicine, but the translation of many promising technologies into the clinic is currently limited by a lack of remote-control inducers that are safe and can be tightly regulated. Here, we developed therapeutically active engineered cells regulated by a control system that is responsive to protocatechuic acid (PCA), a metabolite found in green tea. We constructed multiple genetic control technologies that could toggle a PCA-responsive ON/OFF switch based on a transcriptional repressor from Streptomyces coelicolor. We demonstrated that PCA-controlled switches can be used for guide RNA expression–mediated control of the CRISPR-Cas9 systems for gene editing and epigenetic remodeling. We showed how these technologies could be used as implantable biocomputers in live mice to perform complex logic computations that integrated signals from multiple food metabolites. Last, we used our system to treat type 1 and type 2 diabetes in mice and cynomolgus monkeys. This biocompatible and versatile food phenolic acid–controlled transgenic device opens opportunities for dynamic interventions in gene- and cell-based precision medicine.

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