Illustration by Dante Terzigni

Penn Dental’s Henry Daniell inches closer to the elusive dream of oral insulin.

Ever since the first injection of insulin in 1922, scientists have been trying to figure out how to administer the blood-sugar-regulating hormone in a swallowable form. The history of that quest, as one researcher put it in a late-20th-century appraisal, has been one of “great ambition and continuous failure.” So the treatment of diabetes has long relied on subcutaneous injection, whose drawbacks range from high cost and needle phobia to weight gain and dangerous hypoglycemia.

For more than 15 years, Henry Daniell, the W.D. Miller Professor at Penn’s School of Dental Medicine, has been producing proinsulin (and other therapeutic molecules) within the leaves of genetically engineered lettuce plants [“The Lettuce Cure,” May|Jun 2014]—and this summer his team inched one step closer to treating diabetes with a simple pill.

In a study on diabetic mice, Daniell and Penn Dental colleagues showed that their lettuce-based proinsulin regulated blood sugar quite similarly to the way naturally secreted insulin does in healthy mice. After a 15-minute lag as the freeze-dried lettuce powder passed through the stomach to the small intestine, where gut microbes can cleave the plant cell walls to release the proinsulin within, the diabetic mice regulated their blood sugar without triggering the hypoglycemia characteristic of basic injections—the most common treatment method for most of the world’s roughly 500 million diabetes sufferers, for whom advanced insulin pumps are prohibitively expensive.

In addition to containing all three peptides that are present in natural insulin—one of which is missing from current clinical formulations—the lettuce-based proinsulin was delivered from the gut to the liver, where it appeared to function much the way naturally secreted insulin does. That would explain the happy lack of hypoglycemia, which can occur when insulin is injected directly into the bloodstream. Yet that very biological advantage poses a challenge in drug development because the US Food and Drug Administration (FDA) typically demands evidence of a therapeutic agent’s bioavailability—that is, its measurable presence in the circulatory system.

The bioavailability problem has dogged oral insulin development for decades. But Daniell derives cautious optimism from the FDA’s 2020 approval of Palforzia, a treatment for peanut allergy. When evaluating that agent, which is essentially a minute quantity of defatted peanut flour, “the FDA asked the same question,” Daniell notes. “And the peanut allergy guys from Duke, in the clinical trial, said that the level is so low that you cannot detect it in [blood] plasma.” Although Palforzia has been a commercial disappointment, the regulatory precedent it set could be important, says Daniell. “It’s an example where the FDA has accepted that you don’t have to measure the quantity in the plasma” in order to win approval.

Another of the FDA’s classic concerns has been about the purity of therapeutic agents. Injectable insulin, for instance, is typically produced via yeasts or bacteria that must be removed, as potentially toxic impurities, from the end product. Indeed, that purification process is one reason clinical insulin is so expensive. Under the traditional paradigm, the lettuce cells containing Daniell’s proinsulin could also be viewed as impurities. Yet purifying them out would undercut a critical part of the delivery system, since the lettuce cell walls are precisely what protect the proinsulin cargo from destruction by stomach acids. 

On that front, Daniell takes heart from a regulatory triumph of his own. Last year he led a large team of researchers in a study demonstrating that a chewing gum containing lettuce-produced molecular agents could trap and potentially neutralize the SARS-CoV-2 virus in saliva. On the strength of a preclinical study, the FDA approved the gum for a Phase I/II clinical trial—effectively blessing the presence of lettuce cell material in another precedent that Daniell hopes will help the cause of his oral insulin approach.

Oral insulin still faces significant hurdles. Many previous studies have found that its effectiveness varies widely between subjects. The nonstandard nature of the gut microbiome, which can vary from one person to another, poses a challenge for a delivery method that relies on gut bacteria. And oral insulin’s potential interactions with other food and drink represent another complication.

Yet this treatment’s apparent similarity to the action of naturally secreted insulin is a welcome step forward. And the lettuce-based platform has another attraction. Past attempts to develop oral insulin have failed to advance to the clinic “because of low bioavailability and the 50- to 100-fold higher insulin dose requirement” compared to injections, the researchers noted in their study, published in the July issue of the scientific journal Biomaterials. “[B]ut this concern is addressed by the low cost of insulin produced in plant cells,” they added. Daniell has also demonstrated that his lettuce-produced proinsulin remains pharmacologically active and shelf-stable for a year at ambient temperature.

“This offers, for the first-time, the ability to transport insulin to remote villages in the globe that lack cold storage and transportation facilities,” he says.

“With this delivery system, we change the whole paradigm, not only for insulin,” he adds. “I grew up in a developing country and saw people die because they couldn’t afford drugs or vaccines. For me, affordability and global access to health care are the foundation for my work. And in this case we are making insulin more affordable while significantly improving it. Patients can get a superior drug at a lower cost.”

Daniell now aims to move from mice to canines and humans with Type 2 diabetes. Oral insulin remains a great ambition, but with a bit of luck perhaps a century of “continuous failure” will one day yield to stubborn, stepwise progress. —TP

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