Scientists at Penn’s Institute for RNA Innovation pursue vaccines to stop celiac disease

Jax Bari, an 11-year-old from Philadelphia, shows me a photo of himself. It’s hard to look at; in it, he’s sprawled out on the bathroom floor, sad, exhausted. He says, just hours earlier, he had accidentally consumed gluten while out to eat with his family. What followed was hours of vomiting, diarrhea, and stomach pain.

That was April 2023, the time he’s felt the sickest from eating gluten. “For me, eating can be scary,” said Bari. He can’t go to a friend’s house, enjoy a birthday party, go out to eat with his family, or snack at after-school events without carefully reading food labels, asking a lot of questions, planning, and worrying that he’ll get sick again.

Bari is one of an estimated 3.3-million people in the United States who have celiac disease, a potentially life-threatening autoimmune disease where gluten, a protein in wheat, barley, and rye, causes damage to the small intestine. It’s different and more severe than gluten sensitivity, and it’s not just an allergy. Those with celiac disease cannot process gluten; they can have digestive issues, trouble absorbing the necessary nutrients their bodies need, and potentially lasting damage to their small intestine which can make those absorption issues chronic and lead to cancer.

New research published in the journal Clinical Gastroenterology and Hepatology in December confirmed the understanding that people with celiac disease are more likely to develop lymphoma and small bowel cancer, and also found people with the disease have increased risks of pancreatic, esophageal, gastric, and colonic cancers.

Currently, there’s no treatment for celiac disease aside from avoiding gluten. In situations where someone becomes really dehydrated, the only treatment is giving replacement fluids through an IV.

“I have to eat like everyone else, but there is always a chance that my food might have come into contact with gluten,” said Bari. “If there was a medicine that could allow me to eat gluten or even one that would help reduce my symptoms if I accidentally did, that would change my life.”

One possible answer to that life-changing question? New research is using messenger RNA (mRNA) led by Penn Medicine’s Drew Weissman, MD, PhD, the Roberts Family Professor of Vaccine Research and Jilian Melamed, PhD, research assistant professor of Infectious Diseases.

So far, mRNA has offered a new way to prevent viruses, specifically the SARS-CoV-2 virus that causes COVID-19, thanks to a novel vaccine platform from Weissman and his longtime scientific collaborator at Penn, Katalin Karikó, PhD, an adjunct professor of Neurosurgery. Their discovery earned the pair a Nobel Prize. At Penn and elsewhere, researchers are revamping mRNA to create vaccines for a variety of infectious diseases like norovirus, C. diff, herpes simplex virus 2, and HIV, and trials are underway to put mRNA gene therapy to the test. Researchers like Weissman and Michael J. Mitchell, PhD, an associate professor of Bioengineering at Penn, are even exploring mRNA as a cancer stopper, spurring the body’s immune system to mount robust defenses against cells that are inherently skilled at protecting themselves from humans’ natural defenses.

When it comes to treating celiac disease, the need is different.

“In a way, we want to use mRNA to induce the opposite response you’d want for an infectious disease vaccine,” said Melamed. “For diseases like COVID, you want to induce an infection-fighting response; for celiac disease, we want to stop the immune response already happening in the body.”

The idea is to make what experts call a “tolerizing vaccine,” or a vaccine that would allow someone’s body to tolerate the thing it’s reacting to; in this case, that would be the gluten protein.

When someone with celiac disease consumes gluten, their immune system triggers inflammation and improperly releases antibodies to fight it. These antibodies also destroy the lining of the small intestine, and that destruction impairs the body’s ability to absorb nutrients. What aspect of gluten proteins are improperly seen as a threat? Experts aren’t sure.

“Gluten is not a threat to most people, but as with food allergies, the body’s defenses are signaled and an immune response ensues,” said Melamed. “Ideally, a tolerizing vaccine for celiac would carry information about gluten and teach our immune system to recognize it as safe. Another technique could be using mRNA to somehow induce our immune system to protect or bolster the villi in the small intestine and prevent long-term damage to the digestive system. We’re still in early stages of research and trying to better understand the molecular mechanisms at play.”

Melamed and Weissman’s work is supported by a new $375,000 grant from the Commonwealth of Pennsylvania.

Weissman’s mRNA platform is a good strategy for experts trying to stop celiac disease for the same reason it’s been effective at protecting against viruses: it’s adaptable.

“As far as therapeutics go, the mRNA platform is very plug-and-play; you can use the same basic foundation and make little tweaks to the code, and then send it on its way,” says Weissman. “That’s what made it so useful during the pandemic. Researchers did not need to grow the virus to include in the vaccine and could quickly edit the formula to teach the immune system to recognize different spike proteins in the evolving SARS-CoV-2 virus.”

Lipid nanoparticles (LNP), the concoctions of various fat droplets currently used as the delivery vehicle for mRNA, are also being evaluated for any way they could be altered to either enhance mRNA coded messages or interact directly with the immune system.

“We know that the mRNA-LNP platform is a safe and effective therapeutic technique, but we’re likely far from knowing its full potential,” said Melamed.

Could a treatment for celiac disease lead to quick treatments or vaccines against other food allergies? Is there a one-size-fits-all vaccine on the horizon? Probably not.

“While there are similarities between serious food allergies and celiac disease, we don’t think we’ve identified a single mRNA-LNP formulation that will work for everything,” said Melamed. “We would love if we found a straightforward connection to target, but celiac disease and allergies have their own unique mechanisms at play.”

Weissman himself is no stranger to living with a chronic disease, one specifically that revolves around food. He was diagnosed with type 1 diabetes as a child.

“Having a chronic illness is definitely not easy,” said Weissman. To an outsider, Weissman seems to regard diabetes like an annoying fly buzzing around that he’s forced to occasionally shoo away. He’d rather be speaking to people in his lab about the work or analyzing or designing research than taking a quick break to have a snack or check his blood sugar.

“I got into medicine to help people, and it makes me feel good to know that expanding mRNA research from infectious diseases into chronic diseases could change more lives,” he said. “Maybe someday kids like Jax will be able to go out and eat a piece of pizza with their friends.”

In the meantime, along with raising awareness of celiac disease, 11-year-old Jax Bari has filed a Citizen Petition with the FDA to require food makers to label gluten on all packaged foods in the US. He wants the US to join 87 other countries that have the requirement. Labeling barley, rye, and oats in the US is voluntary.

“Until there’s a treatment for celiac other than a gluten-free diet,” said Bari, “requiring the labeling of gluten grains will have the greatest impact on improving quality of life and safety for Celiacs. Eating without fear is our mission!”