Scientists at The Wistar Institute announced on June 26 that a single injection of a small, circular piece of genetic instructions can produce weight loss and blood glucose control in mouse models for up to 10 times as long as incretin-mimicking drugs such as Ozempic and Wegovy. If successful in clinical trials, this new method could eliminate the need for repeated dosing, which currently limits patient access and adherence to these therapies.
Incretin hormones like GLP-1 and GIP are naturally produced in the body and regulate blood sugar and appetite. Drugs that mimic these hormones have been effective for treating type 2 diabetes and obesity. However, because their native forms break down quickly in the body, current therapies require weekly injections or daily pills—regimens that demand sustained patient compliance and contribute to rebound weight gain or blood glucose issues when patients stop treatment.
"The DNA platform has demonstrated it can do that. Instead of delivering a drug that will get cleared by the body, we're giving cells the instructions to make that drug themselves, and they keep making it," said one researcher involved with the project.
The approach builds on previous Weiner Lab research validated in human patients showing the human body can function as a "factory" to produce long-lasting antibodies. The lab developed an intramuscular DNA electroporation platform where patients receive a shot of plasmid DNA followed by an electrical pulse to help get the instructions into cell nuclei. In earlier trials using this method for COVID-19-neutralizing antibodies, two antibodies were expressed continuously in human subjects for more than 72 weeks.
To adapt this technology for metabolic disease, Gary and colleagues engineered DNA instructions for long-acting incretin hormones called pLincretins. They included an antibody fragment to prevent rapid breakdown of proteins in the body. In preclinical mouse models using electroporation delivery, a single dose produced detectable levels of incretins for up to 70 days with sustained reductions in body weight and blood glucose. In comparison with semaglutide (the active ingredient in Ozempic), mice treated with pLincretins maintained metabolic improvements after observation ended, while those given semaglutide began regaining weight once dosing stopped.
Gary's team also used AI-assisted structural modeling combined with synthetic consensus design to create pSynCretin—a molecule engaging both GLP-1 and GIP receptors simultaneously—which also induced sustained weight loss after just one dose in mouse models.
Gary said she is now pursuing studies on immunological effects of incretin therapy, including its role regarding cancer outcomes: "What I keep coming back to is how much we still don't know about what these molecules are doing beyond weight loss and blood glucose." She added: "It's made me start thinking about the immunological implications of incretin therapy." Gary sees potential applications beyond metabolic disease: "The really amazing part of this research is that once we have this toolkit, we can think about making novel proteins that didn't exist before... The possibilities are really exciting."
