Few medications have gained public attention as quickly as GLP-1 receptor agonists, a class of drugs originally approved by the FDA to treat type 2 diabetes and now widely used for obesity and weight management. While these drugs are effective at controlling blood sugar and supporting weight loss, their widespread use is limited by factors such as high manufacturing costs, delivery methods, and side effects, particularly in low- and middle-income countries.
A new study led by Henry Daniell from the School of Dental Medicine explores an alternative method for delivering two GLP-1 receptor agonists—exenatide and lixisenatide—that are currently only available as injectables. The research, published in Plant Biotechnology Journal, demonstrates that genetically engineered lettuce chloroplasts can produce functional GLP-1 peptides. This innovation could lead to more affordable oral medications for diabetes and obesity.
Oral delivery of peptide drugs has been challenging due to breakdown in the stomach and poor absorption in the gut. Existing oral options like semaglutide require strict fasting protocols to be effective and often cause gastrointestinal side effects such as nausea, vomiting, and diarrhea.
Daniell’s team addressed these issues by engineering lettuce plants to encapsulate exenatide and lixisenatide within plant cells. "We eat plant cells all the time," Daniell said. "And we deliberately chose exenatide and lixisenatide because they have been used very successfully in the clinic and have a long safety record."
This approach protects the peptides from stomach acid degradation because "human enzymes cannot digest plant cells," according to Daniell. Once in the gut, bacteria release enzymes that break down plant cell walls, releasing the therapeutic peptides.
The production method also eliminates certain steps required for conventional GLP-1 receptor agonists, such as post-translational modifications needed to make synthetic peptides functional. "For us, the chloroplasts do this naturally," Daniell said. "Plant cells do these modifications on an everyday basis. And so, the system is already there to make these peptides functional."
Daniell noted that using natural versions of these peptides may reduce side effects seen with current synthetic GLP-1 drugs: "The GI problems are most likely associated with synthetic GLPs," he said, "because such complaints were not frequent with natural GLP-1RAs like lixisenatide or exenatide for the past 45 years."
Cost is another advantage cited by Daniell: "The cost is different because of the simplicity of our approach. How much can you charge for a leaf of lettuce?"
The research team is now preparing additional batches of their plant-based GLP-1 therapies using experience gained from scaling up oral insulin preparations at Penn facilities. "We have learned how to scale up the preparation here at Penn," Daniell said. "We have the facilities to produce early-stage clinical trials."
