A closed-loop synthetic gene circuit for the treatment of diet-induced obesity in mice

Abstract

Diet-induced obesity is a lifestyle-associated medical condition that increases the risk of developing cardiovascular disease, type 2 diabetes and certain types of cancer. Here we report the design of a closed-loop genetic circuit that constantly monitors blood fatty acid levels in the setting of diet-associated hyperlipidemia and coordinates reversible and adjustable expression of the clinically licensed appetite-suppressing peptide hormone pramlintide. Grafting of the peroxisome proliferator-activated receptor-α onto the phloretin-responsive repressor TtgR produces a synthetic intracellular lipid-sensing receptor (LSR) that reversibly induces chimeric TtgR-specific promoters in a fatty acid-adjustable manner. Mice with diet-induced obesity in which microencapsulated cells engineered for LSR-driven expression of pramlintide are implanted show significant reduction in food consumption, blood lipid levels and body weight when put on a high-fat diet. Therapeutic designer circuits that monitor levels of pathologic metabolites and link these with the tailored expression of protein pharmaceuticals may provide new opportunities for the treatment of metabolic disorders.

A Synthetic Mammalian Therapeutic Gene Circuit for Sensing and Suppressing Inflammation

“…Similarly as in other studies, 13 the dynamic range of the genetic circuit in the in vivo conditions did not fully recapitulate the in vitro setting, but nevertheless we have demonstrated that the device enabled a reasonable FI with a relatively low leakage when measuring SEAP as an output (Figures 4E and 4F). When therapeutic proteins were profiled in the serum or peritoneal lavage fluid of mice, a better dynamic range was observed, which was attributed to the lower background ( Figures 5C and 5D).…”

“…10,11 These cells can act as prosthetic devices, which do not require any host genome modification. Of particular interest are sensor-effector designs that can autonomously detect and treat various pathological conditions, such as a malfunction in urate homeostasis, 12 diet-induced obesity, 13 and diabetic ketoacidosis. 14 Recently, an innovative designer cell device to treat experimental psoriasis by converting the disease-relevant inputs into the therapeutic output was presented.…”

Synthetic gene network restoring endogenous pituitary–thyroid feedback control in experimental Graves’ disease

“…for the treatment of gout, metabolic syndrome, and obesity in mice (36,37,43). In this study, we designed a thyroid hormone homeostasis circuit that enables the restoration of the physiological hypothalamus-pituitary-thyroid axis in a mouse model of experimental Graves' disease.…”

Gut hormones such as amylin and GLP-1 in the control of eating and energy expenditure

“…Most importantly, increasing amounts of dietary fat led to an enhanced release of pramlintide that resulted in reduced eating and body weight in mice on a high-fat but not on a low-fat diet. 118 Whether this strategy can be employed clinically needs to be studied in coming years.…”

“…118 The authors of this study produced a self-controlled release device for the amylin analog pramlintide. Cells were manipulated in a way that they contained a closed-loop genetic circuit that constantly monitored blood fatty acid levels, and that was coupled to the coordinated and reversible expression and release of pramlintide.…”