LIGHTING UP THE GUT TO DETECT CELIAC DISEASE

A clinician and scientist collaborate on new methods to diagnose, treat and track celiac disease

For Nielsen Fernandez-Becker, MD, PhD, diagnosing celiac disease at times feels like working in the dark.

When a patient complains of abdominal pain, nausea and diarrhea, Fernandez-Becker typically orders a blood test and an intestinal biopsy to screen for celiac disease — a gut-inflaming autoimmune reaction triggered by gluten, a type of protein found in some grains.

But neither test is completely accurate, especially if someone is already avoiding gluten, minimizing the telltale signs of damage caused by the disease.

“It’s frustrating,” said the gastroenterologist, who leads Stanford Health Care’s celiac disease program. “We don’t have a perfect test that can always tell someone with complete certainty whether they have celiac.”

Now, Fernandez-Becker and longtime collaborator Chaitan Khosla, PhD, are testing a more reliable way to detect the disease with the help of Stanford University’s Innovative Medicines Accelerator. The two are launching a clinical trial of a fluorescent compound that literally lights up a celiac disease-triggering molecule. When a doctor peers at intestinal cells under a microscope, the presence or absence of celiac disease will be clearly illuminated. The team’s initial goal is to improve the diagnosis and monitoring of the disease — but their findings could also lay the groundwork for new treatment strategies.

Celiac disease is one of the world’s most common autoimmune conditions, affecting an estimated 1 in 100 people. In people with celiac disease, the body’s immune system overreacts to gluten. But it’s not gluten that sets off the response — it’s gluten that has been chemically altered by an enzyme called tissue transglutaminase 2, or TG2.

“I got interested in TG2 about 25 years ago when I first started looking at celiac disease. This protein seems to play a very important role in causing celiac disease in patients,” said Khosla, the Wells H. Rauser and Harold M. Petiprin Professor and a professor of chemistry. “It seemed like this might be a good target to make a medicine for celiac disease.”

Khosla was inspired to shift his research to celiac disease after his young son was diagnosed with the condition. He reasoned that there must be a way to stop the immune reaction that causes symptoms. Blocking TG2, for instance, would stop the conversion of gluten to its modified form and prevent the inflammatory immune reaction from taking place.

Roadblocks to celiac solutions

But the enzyme is a tricky target. It doesn’t just hang out in an “on” state, ready to wreak havoc at the first bite of bread. In healthy people, the enzyme is usually off — it’s quiet, inactive, just sitting there. In people with celiac disease, however, TG2 becomes persistently active, modifying gluten and triggering gut inflammation.

Over several decades, Khosla’s laboratory studied how TG2 is activated. His team’s work led to the launching of a company, Sitari Pharma, that exploited their findings to develop a drug that inhibits the active form of the enzyme.

Following the acquisition of Sitari by GlaxoSmithKline, the drug entered early clinical trials as a potential treatment for celiac disease. But after a successful Phase 1 clinical trial, the company repurposed the drug for further studies in a different disease. So, Khosla felt he had no choice but to go back to the drawing board in search of a solution for celiac patients.

The same challenges that Fernandez-Becker faces in initially diagnosing celiac disease also plague clinical trials for drugs designed to treat this condition. Other than asking a patient about their symptoms, how can doctors — without a definitive test for celiac — track whether a drug is working?

“This represented a huge problem for the pharmaceutical industry in developing a celiac medicine,” explained Khosla. “There were no benchmarks to show whether the disease was improving,” he said.

This roadblock led to a new idea for Khosla — one could convert a medicinal TG2 blocker into a kind of tracker. So, Khosla and his students made a new variation of the drug bearing a fluorescent tag that would light up only in the presence of active TG2.

“This could have a profound impact on how we diagnose and treat celiac disease,” said Fernandez-Becker, a clinical professor of gastroenterology and hepatology. “We can give patients a much more definitive answer that, yes, this immune reaction against gluten is causing your symptoms.”

In the new clinical trial, enabled by the Innovative Medicines Accelerator and slated to start once the team receives approval from the Food and Drug Administration, patients will drink a solution containing the TG2-binding molecule a few hours before a scheduled endoscopy, during which doctors collect an intestinal biopsy. If TG2 is switched on, the probe will light it up in the biopsy.

Fernandez-Becker and her colleagues will first study the safety of the probe and then begin asking questions about how well it detects celiac disease and monitors disease progression.

For patients, the potential benefits go well beyond diagnosis. The researchers hope the probe will also show whether a gluten-free diet is working — or if lingering symptoms point to ongoing disease or another condition. That’s a particularly important distinction, Fernandez-Becker said, because some patients continue to struggle even after eliminating gluten — and it’s not always clear why. The presence or absence of TG2 activity could help clarify.

“Right now, we don’t have a way to measure mucosal healing in real time,” Fernandez-Becker said. “But if we could use this to see whether the gut is still inflamed, we’d have a powerful new way to guide treatment.”

Probing for answers

It might also clear a path for future therapies. A definitive test for active TG2 could finally give researchers the biomarker they’ve been missing to study how well TG2-blocking drugs work — it would provide a way to track whether a drug is making a meaningful difference inside the gut, not just easing symptoms on the surface.

“Often times, people begin to heal from celiac disease enough that it’s hard for a pathologist to tell whether their intestines are normal just from a biopsy. With a molecular marker for active TG2, we may be able to give them a much better idea,” Khosla said.

This article was originally published in Stanford Medicine Magazine on Monday, September 22nd.