Novel plant-based approach to a better, cheaper GLP-1 delivery system
Research led by Penn Dental’s Henry Daniell investigates the use of a lettuce-based, plant-encapsulated delivery platform as a new oral delivery of two GLP-1 drugs previously approved by the FDA in injectable form.
3 min. read
Researchers, including Rahul Singh (left), in the Daniell lab’s greenhouse where the production of clinical grade transgenic lettuce occurs.
(Image: Henry Daniell)
Few drugs have entered mainstream awareness as quickly or as dramatically as glucagon-like peptide-1, or GLP-1 receptor agonists. Initially approved by the FDA for the treatment of type 2 diabetes, they have since also transformed the therapeutic landscape of obesity and weight management.
These medications are clearly effective. They stimulate the release of insulin and suppress the release of glucagon, another hormone, to help control blood sugar levels, and they also reduce appetite and delay gastric emptying to aid in weight reduction. However, hurdles to their widespread use, such as manufacturing cost, delivery system, and side effects remain, especially in low- and middle-income countries.
A new study led by Henry Daniell of the School of Dental Medicine investigates a new approach to the oral delivery of exenatide and lixisenatide, two GLP-1 receptor agonists previously approved by the FDA in injectable form, to address these hurdles. The results, published in Plant Biotechnology Journal, show that lettuce chloroplasts can produce functional GLP-1 peptides, paving the way to more affordable and better-tolerated oral medications for diabetes and obesity.
However, the oral delivery of peptides is complicated by both digestion in the stomach and poor absorption in the gut, he explains. And overcoming these hurdles using conventional approaches has been challenging. For example, the recently approved oral formulation of semaglutide—the active ingredient in Ozempic®—requires patients to follow specific fasting and timing instructions (fasting, 4 oz. water, and a 30-minute wait) to be effective, and side effects such as nausea, vomiting, and diarrhea are still common.
Building on his pioneering work using plant encapsulation as a delivery method, Daniell and his team genetically engineered lettuce chloroplasts to express exenatide and lixisenatide, thereby protecting the peptides from degradation in the stomach and facilitating their absorption in the gut.
“We eat plant cells all the time,” says Daniell. “And we deliberately chose exenatide and lixisenatide because they have been used very successfully in the clinic and have a long safety record.”
Incorporating these GLP-1 therapies into the genome of lettuce also bypasses synthesis challenges faced by oral formulations, such as the need to adjust the stomach acid pH to be less acidic to prevent degradation, he explains.
“Human enzymes cannot digest plant cells,” says Daniell. “But when plant cells go to the gut, the bacteria there release enzymes to break down their cell walls.”
Their approach also avoids a step in the production of conventional GLP-1 receptor agonists—the post-translational modifications, or chemical changes made to peptides after synthesis, required to make them functional.
“For us, the chloroplasts do this naturally,” says Daniell. “Plant cells do these modifications on an everyday basis. And so, the system is already there to make these peptides functional.”
This delivery platform also allows the natural versions of these peptides to be used, potentially lowering the risk of side effects, he notes. The current GLP-1 drugs have two artificial amino acids incorporated in them to make them last longer in the body.
“The GI problems are most likely associated with synthetic GLPs,” Daniell says, “because such complaints were not frequent with natural GLP-1RAs like lixisenatide or exenatide for the past 45 years.”
Finally, reducing the steps in the production of GLP-1 receptor agonists also means that the overall cost should be lower. “The cost is different because of the simplicity of our approach. How much can you charge for a leaf of lettuce?” says Daniell.
Daniell and his team are now focused on preparing more batches of their plant-encapsulated GLP-1 receptor agonists, drawing on their experience preparing kilograms of oral insulin.
“We have learned how to scale up the preparation here at Penn,” he says. “We have the facilities to produce early-stage clinical trials.”
Henry Daniell is the W.D. Miller Professor in the Department of Basic & Translational Sciences at the School of Dental Medicine at the University of Pennsylvania.
Rahul Singh is a research associate in Penn Dental’s Department of Basic & Translational Sciences.
This work was supported by NIH grant R01 HL 107904.
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