Innovating the future of esophageal research

A new project is helping scientists develop new therapies for diseases of the esophagus by uniting medical and veterinary science.

The esophagus is an organ with a simple purpose—moving food from our mouths to our stomachs. As a result, it's not an organ most people think about very much. But for millions of Americans, the esophagus is top of mind every single day.

"I guarantee you know people who have esophageal disease," says Evan Dellon, a gastroenterologist at the UNC School of Medicine.

The most common esophageal disease in the country, gastroesophageal reflux disease (also known as GERD or acid reflux), affects about 20% of the population. Barrett's esophagus, a complication of GERD that can be a risk factor for cancer, is also relatively widespread.

Dellon specializes in a disease called eosinophilic esophagitis (EoE), a chronic inflammatory disease that has become much more common in the past couple of decades. Patients with EoE can develop scar tissue around the esophagus that makes it hard to swallow and traps food halfway down. To make matters worse, treating EoE and other esophageal diseases can be complicated, as it's hard to get medication to stick to the inside of the esophagus long enough to be effective before that medication is pushed down into the stomach.

But now, Dellon, along with Anthony Blikslager, a veterinarian at North Carolina State University, are setting out to help researchers test, discover, and study new drugs and treatments for esophageal diseases. Their PROMOTER (Porcine Related apprOach to Multidisciplinary cOllaborative Translational ModEl Research) project will develop models of esophageal disease in pigs, giving scientists an efficient and newly insightful way to investigate these conditions.

This work stemmed, in part, from a North Carolina Translational and Clinical Sciences (NC TraCS) Institute-supported project Dellon and Blikslager worked on with S. Rahima Benhabbour, a biomedical engineer at UNC and NC State, and a former NC TraCS K scholar. In addition, much of the PROMOTER project's work will be supported by NC TraCS.

Dellon hopes that with this new set of tools, scientists can get their research on potential new therapies for esophageal diseases out of the lab and into doctor's offices faster—supporting the millions of Americans who suffer from these conditions.

"What we're lacking is a rapid way to show proof of concept and get treatments into humans sooner...This system is designed to do that."

"The time to get a treatment approved for esophageal conditions is really long. What we're lacking is a rapid way to show proof of concept and get treatments into humans sooner," Dellon says. "This system is designed to do that, to decrease the time it takes to get potential new therapies into human testing and in use by people."

In patients with EoE, a type of white blood cell called an eosinophil starts showing up in the esophagus, where these cells aren't normally found, causing inflammation. This condition is likely caused by food or environmental triggers, Dellon says, and over time, the esophagus develops scar tissue. For patients, this can be debilitating.

"People will get food stuck so badly they can't get it up or down, and then they end up in the emergency room. That's often how people are diagnosed," Dellon says. "They need an emergency endoscopy to pull the food out, and it's very painful. People modify their diet, they're afraid of eating in public because of food sticking and having to bring it back up."

Until recently, clinicians had just a few options available to treat patients with the disease. Topical steroids can help reduce some of the inflammation, but getting those steroids onto the inside wall of the esophagus is a challenge. Some patients use an inhaler to try and get medication into their esophagus by puffing into their mouth and swallowing without breathing that medication into their lungs, while others mix medication with a syrup that can stick to the esophagus after being swallowed. But Dellon says that even the stickiest of these medicated syrups can only linger for about 15 seconds before the esophagus pushes them down into the stomach.

The FDA recently approved a pre-mixed medicated steroid syrup for people with EoE, approved for 12 weeks of use. Dupilumab, an anti-inflammatory monoclonal antibody delivered as a weekly shot, was also recently approved for patients with EoE. In addition, clinicians can work with patients to eliminate potential allergens in their diet or prescribe medications like proton pump inhibitors to help prevent inflammation.

But a few years ago, Dellon and Blikslager teamed up with Benhabbour to try and develop a new way of getting medications to stick to the inside lining of the esophagus. The research team received an NC TraCS/NC State University Collaborative Pilot grant and a UNC Innovation Pilot Award to support this work.

Benhabbour studies novel methods of drug delivery, and the team wanted to create a device that could be placed in the esophagus to release a continuous dose of medication. They ended up developing two prototypes: a ring that could be placed into the esophagus to deliver a steady dose of medication, and a string that could be swallowed at night and pulled out in the morning to release medication overnight. To test these devices, the team turned to pigs.

Pigs offer a uniquely useful model for studying the human esophagus. For one, a pig's esophagus is roughly the same size as a human's esophagus. As a result, researchers can easily use tools developed for people, like endoscopes, to study a pig's esophagus, too.

In contrast, mice, which are frequently used in medical research, are far too small to be scoped. Many small animals also have keratin on the lining of their esophagus (similar to the tough coating of the skin), while a pig's esophageal lining looks more like humans, which lack keratin, Dellon says. Similarly, Dellon says that pigs have submucosal glands behind their esophageal walls, an important part of the human esophageal structure.

Dellon learned about using pigs for this kind of research from colleagues like Blikslager and Liara Gonzalez, another veterinarian at NC State, as well as Katherine Garman, a gastroenterologist at Duke, who have all used the animals to study gastrointestinal disease.

When it came to testing the team's new devices, using pigs to study the esophagus helped them assess how well the devices worked and troubleshoot the design. They first developed the drug-dispensing rings—but after testing the rings in some pigs, they found that the pigs' esophagi were strong enough to push the devices down into the stomach.

"The esophagus is a muscular organ, and so in relatively short order it just squeezed the rings right out of the esophagus," Dellon says. "They wouldn't stay in place."

This insight prompted them develop the strings instead, which they again tested in pigs. They loaded up these strings with fluticasone, a common steroid, and got some promising results.

"In the pigs, we were able to show that it worked," Dellon says. "We could measure the drug in the esophagus."

While neither of these devices ended up moving past the prototype stage, the idea of using pigs to study esophageal disease has stuck. In 2022, Dellon, Blikslager, and some colleagues published a paper in the journal Frontiers in Allergy showing how they could cause pigs to develop many of the signs of EoE by exposing them to egg white protein. By sensitizing the pigs slowly to the egg white over time and then feeding them a lot of it (the "challenge" phase), the researchers could induce an allergic reaction similar to EoE in the pig's esophagus. This study was funded by the UNC Center for Gastrointestinal Biology and Disease.

That paper remarked that pigs are "a valuable animal model for biomedical research on EoE" and that this pig model of the disease could "drive translational biomedical research to develop urgently needed treatment strategies for EoE."

The PROMOTER study will drive this science forward. The project is supported by an RC2 grant from the National Center for Advancing Translational Science, a division of the National Institutes of Health, which is only available to researchers at institutions with a Clinical and Translational Science Award hub like NC TraCS. TraCS experts also helped Dellon and Blikslager with proposal development, and will support the team with biostatistics assistance, ethical training, evaluation and sustainability plans, and additional services.

"The idea is to generate a set of scientific resources that we would share with the broader scientific community."

The team will develop various disease models in pigs—essentially, developing methods to induce different types of esophageal diseases in pigs. In addition to inflammation, the team will focus on acute injuries, such as esophageal ulcers, radiation injuries, and stricturing, which is when the esophagus gets too narrow. With these models, researchers could study how different esophageal diseases progress, for example, or how well a potential new drug might work.

Alongside these disease models, Dellon, Blikslager, and their colleagues will study the ins and out of the pig esophagus, including genome sequencing, proteomics, immunologic analysis, and single-cell sequencing, where they can pinpoint which cells are expressing which genes.

All this information will be available to researchers around the world to support their own work. Scientists from all over will also be able to contract with the team in North Carolina to induce these disease models in pigs for different research projects.

"The RC2 grant is really a discovery-based grant," Dellon says. "The idea is to generate a set of scientific resources that we would share with the broader scientific community."

And with those resources, researchers will get a new leg up on esophageal disease—helping them uncover what causes these illnesses, how they manifest over time, and, most importantly, how to support the millions of people who suffer from them every day.