Caleb Sooknanan ‘20

Hepatogenous diabetes is a condition often characterized by the comorbid presence of type 2 diabetes with chronic liver disease. A major factor in this condition is insulin resistance (IR), an asymptomatic disease state in which impaired insulin signaling causes organ dysfunction. Current therapies that target IR are limited and generally inapplicable for patients with liver disease. Dr. Shuai Xue and researchers at East China Normal University in China used oleanolic acid (OA) — a chemical compound used as a safe treatment in many liver disorders — along with glucagon-like-peptide 1 (GLP-1) to create a therapeutic gene circuit in hopes of improving bodily functions.

To design the necessary gene circuit, the researchers first implanted immunoprotective microcapsules containing OA-regulated short human GLP-1 (shGLP-1)-expressing cells into a mouse model wih hepatogenous diabetes. The researchers thereby integrated a doxycycline (Dox)-induced regulatory element into the circuit, which would enable the rapid termination of transcription and GLP-1 production. To analyze the long-term therapeutic efficacy of the OA-inducible Dox-repressible shGLP-1 expression device, the researchers uploaded their circuit to the Sleeping Beauty transposon system, which allows for the stable introduction of the circuit into mammalian cells.

The mice that received treatment showed significant reduction in food and water intake, as well as decreased body weight changes. Histological liver analyses also suggested a significant decrease in fat build-up in the hepatocytes of treated mice. The researchers were able to evaluate some of the synthetic circuit’s benefits. For example, both OA and GLP-1 target IR, thereby allowing the treatment of pathogenic determinants at the earliest possible stage. Also, microencapsulated human designer cells serve clinically validated and immunoprotective purposes, and the Dox-triggered safety switch engineered into the designer cell architecture enables precise control of gene circuit function in case of unprecedented cases.

This form of synthetic design could be optimized into a technical platform for future clinical human studies, thereby revolutionizing synthetic biology and its applications.

References:

1. S. Xue, et al., A Synthetic-Biology-Inspired Therapeutic Strategy for Targeting and Treating Hepatogenous Diabetes. Molecular Therapy 25, 443 – 455 (2017). doi: 10.1016/j.ymthe.2016.11.008
2. Image retrieved from: https://putthatcheeseburgerdown.com/2016/02/14/5-facts-you-may-not-know-about-diabetes/