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Published on: November 4, 2018
A Synthetic-Biology-Inspired Therapeutic Strategy for Targeting and Treating Hepatogenous Diabetes
Shuai Xue1, Jianli Yin1, Jiawei Shao1
1Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Dongchuan Road 500, Shanghai 200241, China.
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.
Insights
This study engineered a synthetic gene circuit to treat hepatogenous diabetes by combining oleanolic acid and glucagon-like-peptide 1 (GLP-1). The novel approach demonstrated synergistic therapeutic effects, improving metabolic failures in mice.
Area of Science:
- Biotechnology
- Metabolic Diseases
- Pharmacology
Background:
- Hepatogenous diabetes involves type 2 diabetes and liver disease, primarily driven by insulin resistance (IR).
- Current IR pharmacotherapies are limited, especially for patients with liver conditions.
- Oleanolic acid (OA) is a plant-derived compound used in traditional medicine for liver disorders.
Purpose of the Study:
- To engineer a synthetic gene circuit for synergistic treatment of hepatogenous diabetes.
- To combine the therapeutic actions of oleanolic acid (OA) and glucagon-like-peptide 1 (GLP-1) for enhanced efficacy.
- To investigate the potential of engineered gene circuits in treating multifactorial diseases.
Main Methods:
- Utilized a synthetic-biology-inspired design principle to create a therapeutic gene circuit.
- Engineered the circuit for OA-triggered expression of short human GLP-1 (shGLP-1).
- Tested the engineered circuit in hepatogenous diabetic mouse models.
Main Results:
- The OA-triggered shGLP-1 gene circuit rapidly and simultaneously attenuated disease-specific metabolic failures in mice.
- Monotherapy with OA or shGLP-1 did not achieve the same level of therapeutic effect.
- Demonstrated synergistic therapeutic outcomes through multiplexed targeting.
Conclusions:
- Rationally engineered synthetic gene circuits can effectively treat multifactorial diseases like hepatogenous diabetes.
- This approach enables synergistic therapeutic effects by combining the actions of different drugs.
- Highlights the potential of synthetic biology for developing novel treatments for complex metabolic disorders.
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