Developing GLP-1 Producing Genetically Engineered Probiotics for Treatment of Metabolic Diseases

About This Grant

PROJECT SUMMARY / ABSTRACT The increasing prevalence of metabolic diseases such as type 2 diabetes mellitus (T2DM), obesity, and associated cardiovascular risks represents a major global health challenge. The glucagon-like peptide-1 (GLP-1) is a peptide hormone secreted in response to food intake and neuroendocrine stimulation. As an incretin hormone, GLP-1 plays a crucial role in glucose homeostasis, insulin secretion, and appetite regulation. The synthetic GLP-1 receptor agonists (GLP-1RAs) which mimic native GLP-1's pharmacological functions with extended half-lives and increased biological activity have emerged as a leading treatment for type 2 diabetes and obesity. While GLP-1RAs show promising results in various therapeutic areas beyond diabetes and obesity, significant challenges remain, which include poor patient compliance and high discontinuation rates, due to requirement of frequent injections, side effects, accessibility issue due to global shortage, and high-cost barriers. The goal of this project is to develop engineered probiotics capable of producing and continuously delivering GLP-1 both locally in the gastrointestinal (GI) tract and systemically, to overcome these challenges of GLP-1RAs-based therapies. Moreover, increasing evidence indicates that the gut microbiome plays a crucial role in the pathogenesis of metabolic diseases through multiple interconnected mechanisms and probiotics have been shown beneficial in managing these conditions; thus, engineered probiotics not only deliver GLP-1 but also could potentially modulate gut microbiota, improving intestinal health and immune function. We have developed an innovative, probiotics-based platform technology for the oral delivery of therapeutic proteins that targets several challenging chronic diseases. Our recent published results provide proof-of-concept for the feasibility of using Lactobacillus as a live vector to deliver peptides and proteins, demonstrating enhanced tissue bioavailability and efficacy. In this application, we plan to construct and characterize the engineered Lactobacillus probiotics to produce and secrete biologically active GLP-1 in the GI tract and systemically (Aim 1) and evaluate the efficacy of GLP-1 producing bacteria in the animal model of T2DM (Aim 2). The successful development of engineered bacteria for GLP-1 delivery could revolutionize diabetes treatment and have far-reaching implications in medicine. This approach could significantly improve patient adherence and quality of life by replacing frequent injections with oral administration, while providing sustained GLP-1 production for better glycemic control. It may reduce side effects and treatment costs, enabling more accessible and personalized therapies. Completion of these studies will position us to initiate Phase II studies including pharmacokinetics, biodistribution, toxicology, formulation and scaled-up GMP production of engineered probiotics producing GLP-1 for clinical application.