Pharmaceutically controlled designer circuit for the treatment of the metabolic syndrome

Abstract

Synthetic biology has significantly advanced the design of genetic devices that can reprogram cellular activities and provide novel treatment strategies for future gene-and cell-based therapies. However, many metabolic disorders are functionally linked while developing distinct diseases that are difficult to treat using a classic one-drug-one-disease intervention scheme. For example, hypertension, hyperglycemia, obesity, and dyslipidemia are interdependent pathologies that are collectively known as the metabolic syndrome, the prime epidemic of the 21st century. We have designed a unique therapeutic strategy in which the clinically licensed antihypertensive drug guanabenz (Wytensin) activates a synthetic signal cascade that stimulates the secretion of metabolically active peptides GLP-1 and leptin. Therefore, the signal transduction of a chimeric traceamine-associated receptor 1 (cTAAR1) was functionally rewired via cAMP and cAMP-dependent phosphokinase A (PKA)-mediated activation of the cAMP-response element binding protein (CREB1) to transcription of synthetic promoters containing CREB1-specific cAMP response elements. Based on this designer signaling cascade, it was possible to use guanabenz to dose-dependently control expression of GLP-1-Fc mIgG -Leptin, a bifunctional therapeutic peptide hormone that combines the glucagon-like peptide 1 (GLP-1) and leptin via an IgG-Fc linker. In mice developing symptoms of the metabolic syndrome, this three-in-one treatment strategy was able to simultaneously attenuate hypertension and hyperglycemia as well as obesity and dyslipidemia. Using a clinically licensed drug to coordinate expression of therapeutic transgenes combines drug-and genebased therapies for coordinated treatment of functionally related metabolic disorders. T he metabolic syndrome is a combination of disorders and risk factors including hypertension, hyperglycemia, obesity, and dyslipidemia that show an extremely complex and littleunderstood interdependent pathophysiology and collectively increase the risk for cardiovascular diseases that remain the prime cause of mortality worldwide (1-8). Currently available therapies independently target each of the individual disorders and risk factors, but a well-coordinated collective treatment strategy does not exist (2). We have therefore designed a synthetic signaling cascade in which a clinically licensed small-molecule drug finetunes expression of therapeutic transgenes. The combination of drug-and gene-based therapies enables simultaneous treatment of all key metabolic syndrome pathologies. Guanabenz (Wytensin) is a clinically licensed antihypertensive drug that is thought to activate alpha-2-selective adrenergic receptors in the central nervous system, thereby reducing the sympathetic outflow to heart, kidney, and peripheral vasculature and decreasing the systolic and diastolic blood pressure (9). Recently, guanabenz was also identified as an agonist of the trace amine-associated receptor 1 (TAAR1) (10). TAARs are G protein-coupled receptors located in the neu...

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