Scientists at the Wistar Institute have shown that a single injection of a small circular gene directive in a mouse model can produce weight loss and blood sugar control that lasts up to 10 times longer than incretin mimetics such as Ozempic and Wigovy. If proven successful in clinical trials, this new delivery method could eliminate the need for repeated doses that currently limit patient access and compliance with these treatments.
Incretin hormones, such as GLP-1 and GIP, are naturally produced in the body and regulate blood sugar levels and appetite. Drugs that mimic them have proven highly effective in treating type 2 diabetes and obesity. However, because their natural forms are quickly degraded in the body, current treatments require weekly injections or daily tablet administration, require continued patient compliance, and can cause rebound weight gain and blood sugar dysregulation when patients discontinue treatment.
What we’re trying to do here is simple. Once we deliver a drug, we want it to remain effective for a very long time. ”
Dr. Ebony Gary, assistant professor in the David B. Weiner Laboratory at the Wistar Institute Center for Vaccines and Immunotherapy, and lead author of the study
“The DNA platform has demonstrated that it can do that. Instead of delivering a drug that is removed from the body, we instruct the cell to make the drug itself, and the cell continues to make it.”
Her team’s approach builds on research from the Wiener Institute that has already been validated in human patients, showing that the human body can act as a “factory” to produce long-lasting antibodies. This laboratory has developed an intramuscular DNA electroporation platform. This allows patients to receive a shot of plasmid DNA (genetic instructions) followed by an electrical pulse that takes the instructions into the nucleus of the body’s cells, where the information can be read. Weiner and his colleagues used this method to deliver “instructions” for COVID-19-neutralizing antibodies to patients. In Phase 1 clinical trials, two of the antibodies were continuously expressed in human subjects for more than 72 weeks.
To adapt this platform to metabolic diseases, Gary and her colleagues designed DNA instructions for the long-acting incretin hormones GLP-1 and GIP, called pLincretins. Importantly, the instructions include an antibody fragment that helps prevent the protein from being broken down rapidly in the body, as is the case with current incretin mimetics. When tested in a preclinical mouse model of diabetes using electroporation, a single dose of p-linked cretin produced detectable levels of incretin for up to 70 days and promoted sustained reductions in body weight and blood sugar levels. In a direct comparison with semaglutide (Ozempic’s active ingredient), mouse models treated with a single dose of the scientist’s DNA construct maintained improved metabolism after the observation period, whereas mouse models treated with semaglutide began to regain weight as soon as the treatment was discontinued.
The scientists then used an approach called AI-assisted structural modeling and synthetic consensus design to create a new molecule called pSynCretin. The research team identified structural elements common to GLP-1, GIP, and existing incretin drugs and combined them to design a single protein that can engage GLP-1 and GIP receptors simultaneously (similar to how Mounjaro works). A single dose of pSynCretin also induced sustained weight loss in a mouse model.
Gary and members of the Weiner lab are currently conducting research on the immunological effects of incretin therapy, including its potential role in altering cancer outcomes. Clinical data shows that patients taking incretin drugs experience improvement in chronic inflammatory conditions such as arthritis and psoriasis. This raises new questions about the relationship between metabolism and immune function, and Gary believes the DNA platform can help answer them.
“What I always think about is how much we still don’t know about what these molecules do other than weight loss and blood sugar levels,” Gary said. “We now have a lot of data from patients in the clinic about incretin therapy. They’re just taking these drugs that we think of as weight loss drugs or diabetes drugs, but they’re also impacting chronic inflammatory diseases like arthritis and psoriasis. This got me thinking about the immunological effects of incretin therapy.”
Gary also believes that DNA delivery platforms have the potential to expand far beyond metabolic diseases. The same delivery system that enables long-term incretin production in the body could potentially be applied to a wide range of therapeutic proteins needed to treat chronic diseases.
“What’s really great about this work is that once you have this toolkit, you can think about creating new proteins that didn’t exist before and engineering them from the ground up to do exactly what you want them to do,” Gary said. “The possibilities are really exciting.”
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Reference magazines:
Gary, EN; Others. (2026). Engineering single-dose plasmid DNA for sustained in vivo delivery of designer incretins. Biotechnology trends. DOI: 10.1016/j.tibtech.2026.05.023. https://www.sciencedirect.com/science/article/pii/S0167779926002362
