A Synthetic-Biology-Inspired Therapeutic Strategy for Targeting and Treating Hepatogenous Diabetes.
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.
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Dongchuan Road 500, Shanghai 200241, China.
Shuai
S
Xue
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Dongchuan Road 500, Shanghai 200241, China.
Jianli
J
Yin
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Dongchuan Road 500, Shanghai 200241, China.
Jiawei
J
Shao
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Dongchuan Road 500, Shanghai 200241, China.
Yuanhuan
Y
Yu
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Dongchuan Road 500, Shanghai 200241, China.
Linfeng
L
Yang
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Dongchuan Road 500, Shanghai 200241, China.
Yidan
Y
Wang
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Dongchuan Road 500, Shanghai 200241, China; Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, 4058 Basel, Switzerland.
Mingqi
M
Xie
Department of Biosystems Science and Engineering, ETH Zurich, Mattenstrasse 26, 4058 Basel, Switzerland.
Martin
M
Fussenegger
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Dongchuan Road 500, Shanghai 200241, China. Electronic address: hfye@bio.ecnu.edu.cn.
Haifeng
H
Ye
D000818:Animals; D060846:Cell Engineering; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000175:diagnosis / Q000209:etiology* / Q000378:metabolism / Q000628:therapy*; D004195:Disease Models, Animal; D015195:Drug Design; D005786:Gene Expression Regulation / Q000187:drug effects; D053263:Gene Regulatory Networks / Q000187:drug effects; D005818:Genetic Engineering; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007333:Insulin Resistance; D008107:Liver Diseases / Q000150:complications* / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009828:Oleanolic Acid / Q000494:pharmacology / Q000627:therapeutic use; D058615:Synthetic Biology
D009828:Oleanolic Acid; D052216:Glucagon-Like Peptide 1
biomedical engineering; gene and cell-based therapy; glucagon-like peptide-1; hepatogenouse diabetes; oleanolic acid; prosthetic gene network; synthetic biology; synthetic gene circuit