Single-dose plasmid DNA delivers sustained GLP-1/GIP agonists, reducing obesity in mice

Current incretin mimetic drugs have revolutionized treatment for obesity and type 2 diabetes, yet they face significant challenges including high production costs, frequent dosing requirements, and patient compliance issues. Furthermore, weight regain often occurs upon cessation of therapy. Plasmid DNA delivery offers a compelling alternative, having demonstrated the ability to provide sustained, long-term expression of therapeutic proteins, such as monoclonal antibodies, for over a year in humans. This approach could overcome the limitations of traditional peptide therapeutics by enabling a single administration to provide durable therapeutic effects, addressing the critical need for more convenient and persistent metabolic disease management.

Researchers engineered plasmid-encoded long-acting incretins (pLincretins) by fusing cleavage-resistant glucagon-like peptide-1 (GLP-1) and gastric inhibitory polypeptide (GIP) analogues with IgG heavy chain (Fc) components. These plasmids were delivered to diet-induced obese mice via a single administration using a clinically validated electroporation device. Building on this, an AI-guided protein modeling and synthetic consensus approach was used to design a novel dual GLP-1R/GIPR agonist, named pSynCretin. The primary endpoints included assessing sustained expression, and measuring changes in body weight, food intake, and blood glucose levels in the treated mice.

A single administration of the engineered plasmid DNA successfully drove sustained expression of the incretin mimetics in vivo. This durable expression translated into significant and durable reductions in body weight, food intake, and blood glucose levels in the diet-induced obese mice. The initial pLincretins demonstrated robust efficacy, establishing the feasibility of the DNA-launched approach. Further refinement using AI-guided protein modeling led to the development of pSynCretin, a dual GLP-1R/GIPR agonist. This optimized construct demonstrated enhanced GLP-1R avidity compared to its predecessors.

Importantly, pSynCretin induced potent weight loss in vivo, showcasing the power of rational design in this novel delivery platform. These findings collectively establish DNA-launched incretin mimetics as a highly promising therapeutic tool, combining the potency of next-generation metabolic hormones with the inherent durability, safety, and translational feasibility offered by plasmid delivery systems.