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.
Keywords: Adeno-associated virus; Diabetes mellitus; Exendin-4; Salivary glands.
Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.