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  • A Synthetic-Biology-Inspired Therapeutic Strategy for Targeting and Treating Hepatogenous Diabetes.

A Synthetic-Biology-Inspired Therapeutic Strategy for Targeting and Treating Hepatogenous Diabetes.

Molecular therapy : the journal of the American Society of Gene Therapy (2017-02-06)
Shuai Xue, Jianli Yin, Jiawei Shao, Yuanhuan Yu, Linfeng Yang, Yidan Wang, Mingqi Xie, Martin Fussenegger, Haifeng Ye
ABSTRACT

Hepatogenous diabetes is a complex disease that is typified by the simultaneous presence of type 2 diabetes and many forms of liver disease. The chief pathogenic determinant in this pathophysiological network is insulin resistance (IR), an asymptomatic disease state in which impaired insulin signaling in target tissues initiates a variety of organ dysfunctions. However, pharmacotherapies targeting IR remain limited and are generally inapplicable for liver disease patients. Oleanolic acid (OA) is a plant-derived triterpenoid that is frequently used in Chinese medicine as a safe but slow-acting treatment in many liver disorders. Here, we utilized the congruent pharmacological activities of OA and glucagon-like-peptide 1 (GLP-1) in relieving IR and improving liver and pancreas functions and used a synthetic-biology-inspired design principle to engineer a therapeutic gene circuit that enables a concerted action of both drugs. In particular, OA-triggered short human GLP-1 (shGLP-1) expression in hepatogenous diabetic mice rapidly and simultaneously attenuated many disease-specific metabolic failures, whereas OA or shGLP-1 monotherapy failed to achieve corresponding therapeutic effects. Collectively, this work shows that rationally engineered synthetic gene circuits are capable of treating multifactorial diseases in a synergistic manner by multiplexing the targeting efficacies of single therapeutics.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Poly-L-lysine hydrobromide, mol wt 15,000-30,000 by viscosity
Millipore
Glucagon Like Peptide-1 (Active) ELISA, This Glucagon Like Peptide-1 (Active) ELISA is used to measure & quantify Glucagon Like Peptide-1 levels in Metabolism & Endocrine research.
SAFC
Insulin, Human Recombinant, for research or for further manufacturing use, dry powder