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Development of an adenoviral vector expressing glucagon-like peptide-1 for gene therapy in diabetes Lee, Corinna Wai Kwan

Abstract

Type 2 diabetes (T2D), a chronic metabolic disorder characterized by hyperglycemia, is growing in prevalence in both young and old people worldwide. One of the current treatments for T2D involves the use of oral hypoglycemic medications that stimulate insulin secretion from pancreatic P-cells. However, these drugs risk inducing hypoglycemia and, as p-cell function declines over time, lose their effectiveness. An attractive alternative for the treatment of T2D is glucagon-like peptide-1 (GLP-1), a gut hormone with a variety of anti-diabetic properties including stimulation of glucosedependent insulin secretion and enhancement of P-cell mass. However, the clinical use of GLP-1 is limited due to its rapid degradation, primarily by dipeptidyl peptidase IV (DPIV). As a result, continuous administration of GLP-1 is necessary to maintain its therapeutic effect. Gene therapy may represent a promising alternative approach for achieving long-term automatic release of GLP-1 from cells in the body. In this thesis, the efficacy of in vitro and in vivo GLP-1 gene transfer to the liver using an adenoviral vector expressing GLP-1 and its effects on glucose homeostasis in diabetic db/db mice was examined. A replication-deficient adenoviral vector was constructed to express DPIVresistant GLP-1 under the regulation of a liver-specific, glucose-responsive L-type pyruvate kinase (LPK) promoter (AdLPK-GLP-1). In vitro transduction of AdLPK-GLP-1 in hepatocytes and nonhepatocytes induced immunoreactive and bioactive GLP-1 production in a liver-specific and dosedependent manner. Furthermore, when these transduced hepatocytes were transplanted into the peritoneal cavity or under the kidney capsule of normal mice, an ~2-fold increase in fasting plasma GLP-1 levels was observed. However, this approach was not effective in improving glucose homeostasis in severely diabetic db/db mice. Moreover, intravenous delivery of AdLPK-GLP-1 in normal mice and rats did not result in an increase in fasting plasma GLP-1 levels. Thus while a virus was generated that is capable of inducing hepatocytes to produce GLP-1, additional studies will be required to demonstrate a therapeutic effect with this agent.

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