Junhong Wang1, Feng Wang2, Jing Xu1, Shimei Ding1, Yonghong Guo3. 1. Department of Endocrine, The Second Hospital, Medical College of Xi'an Jiaotong University, Xi'an 710004, China. 2. Department of Nutrition and Food Hygiene, The Fourth Military Medical University, Xi'an 710032, China. 3. Department of Infectious Disease, The Second Hospital, Medical College of Xi'an Jiaotong University, Xi'an 710004, China. Electronic address: xiaoqing9759@sina.com.
Abstract
AIM: Exendin-4 (Ex-4) is an agonist of the glucagon-like peptide 1 (GLP-1) receptor, approved for the treatment of type 2 diabetes (T2DM). Several strategies have been tried to develop stable and efficacious Ex-4 expression systems. The purpose of the current study was to determine whether double-stranded adeno-associated virus (dsAAV)-mediated in vivo expression of exendin-4 in salivary glands (SG), improves pathology in the Sprague-Dawley (SD) rat model of diabetes mellitus (DM). METHODS: The effects of Ex-4 expression by recombinant dsAAV-NT4-Ex-4 were evaluated in vitro compared with a single-strand (ss) AAV. The dsAAV was delivered into SGs and the blood glucose and insulin levels were assessed in a rat model of DM. RESULTS: DsAAV-NT4-Ex-4 virus induces significant exendin-4 expression in vitro. Furthermore, Ex-4 expressed from dsAAV virus in SGs enhances insulins secretion in vivo and significantly controls the onset of hyperglycemia in rat model of DM. CONCLUSIONS: Results suggest that sustained secretion of Ex-4 following dsAAV-mediated gene therapy is feasible. SGs appear to be promising targets with potential clinical applicability for the treatment of DM. This represents the example of a successful use of Ex-4 for diabetes therapy, providing support for direct AAV-mediated in vivo as an easy, safe and efficient therapeutic strategy.
AIM: Exendin-4 (Ex-4) is an agonist of the glucagon-like peptide 1 (GLP-1) receptor, approved for the treatment of type 2 diabetes (T2DM). Several strategies have been tried to develop stable and efficacious Ex-4 expression systems. The purpose of the current study was to determine whether double-stranded adeno-associated virus (dsAAV)-mediated in vivo expression of exendin-4 in salivary glands (SG), improves pathology in the Sprague-Dawley (SD) rat model of diabetes mellitus (DM). METHODS: The effects of Ex-4 expression by recombinant dsAAV-NT4-Ex-4 were evaluated in vitro compared with a single-strand (ss) AAV. The dsAAV was delivered into SGs and the blood glucose and insulin levels were assessed in a rat model of DM. RESULTS: DsAAV-NT4-Ex-4 virus induces significant exendin-4 expression in vitro. Furthermore, Ex-4 expressed from dsAAV virus in SGs enhances insulins secretion in vivo and significantly controls the onset of hyperglycemia in rat model of DM. CONCLUSIONS: Results suggest that sustained secretion of Ex-4 following dsAAV-mediated gene therapy is feasible. SGs appear to be promising targets with potential clinical applicability for the treatment of DM. This represents the example of a successful use of Ex-4 for diabetes therapy, providing support for direct AAV-mediated in vivo as an easy, safe and efficient therapeutic strategy.
Authors: Bruce J Baum; Ilias Alevizos; John A Chiorini; Ana P Cotrim; Changyu Zheng Journal: Expert Opin Biol Ther Date: 2015-07-06 Impact factor: 4.388