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

• Published in: Molecular therapy Vol. 25; no. 2; pp. 443 - 455
• Main Authors: Xue, Shuai, Yin, Jianli, Shao, Jiawei, Yu, Yuanhuan, Yang, Linfeng, Wang, Yidan, Xie, Mingqi, Fussenegger, Martin, Ye, Haifeng
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-02-2017; Elsevier Limited; American Society of Gene & Cell Therapy
• Subjects: Animals; Biology; biomedical engineering; Cell Engineering; Cell Line; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - diagnosis; Diabetes Mellitus, Type 2 - etiology; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - therapy; Disease Models, Animal; Disease resistance; Drug Design; Drug therapy; Experiments; gene and cell-based therapy; Gene expression; Gene Expression Regulation - drug effects; Gene Regulatory Networks - drug effects; Genetic Engineering; Glucagon; Glucagon-Like Peptide 1 - pharmacology; Glucagon-Like Peptide 1 - therapeutic use; glucagon-like peptide-1; hepatogenouse diabetes; Humans; Hyperglycemia; Insulin; Insulin Resistance; Kinases; Liver diseases; Liver Diseases - complications; Liver Diseases - metabolism; Male; Medicinal plants; Metabolism; Metabolites; Mice; Mice, Transgenic; Oleanolic acid; Oleanolic Acid - pharmacology; Oleanolic Acid - therapeutic use; Original; Pancreas; Peptides; Plants; prosthetic gene network; Proteins; R&D; Research & development; Signal transduction; Software; Synthetic Biology; synthetic gene circuit; China; synthetic biology; biomedical engineering; oleanolic acid; glucagon-like peptide-1; prosthetic gene network; synthetic gene circuit; gene and cell-based therapy; hepatogenouse diabetes
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1016/j.ymthe.2016.11.008

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.
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Ye and colleagues describe a promising and realistic therapeutic strategy for the clinical application of synthetic-biology-based and oleanolic-acid-controlled gene circuits for treating hepatogenous diabetes, the currently frequently discussed disease profile characterized by the simultaneous presence of diabetes mellitus, chronic liver diseases, and insulin resistance.