HMN 2026: How Discovery of BIRC3 gene variants in Crohn’s disease yields a druggable pathway

Researchers from The Hospital for Sick Children (SickKids) in Toronto have found a previously unknown genetic cause of Crohn’s disease and uncovered how those changes trigger inflammation through a key immune pathway. The findings, published in Gastroenterology and involving teams from eight countries, will guide more precise treatments and improve the ability to match patients to therapies based on their unique biology.

“We’ve brought together genetics, RNA sequencing, proteomics and more to try for the first time to map the complete disease pathway, and it’s turned into a remarkable precision medicine story,” says lead author Dr. Aleixo Muise, senior scientist in the Cell & Systems Biology program, staff gastroenterologist and co-director of the Inflammatory Bowel Disease (IBD) Centre at SickKids.

“In our SickKids clinic, we want to find the right drug for each person based on their body’s unique signature. That’s why this paper is so exciting: We have pinpointed a druggable pathway.”

Confronting a rising global health problem

IBD is increasing worldwide and across all age groups, including in countries where it was previously rare. Crohn’s disease, the main type of IBD, is estimated to affect about 5 million people, a number expected to grow as it becomes more common in developing nations.

Canada has long had one of the highest rates of IBD in the world, and—early next decade—it’s expected that one in 100 people will be affected. At the SickKids IBD Centre, clinicians support about 1,500 patients each year, reflecting on how the disease is appearing earlier in life.

At his clinic, Muise provides care for about 150 infants and toddlers younger than age two.

“We weren’t seeing this as little as 10 years ago, so it is a very concerning trend,” says Muise, who is also a Canada Research Chair in pediatric IBD.

Current treatments for IBD tend to work in only half of patients, and responses range widely from person to person. This underscores the complexity of IBD, which is influenced by the environment, the gut microbiome, the immune system and DNA.

Identifying a new genetic cause of Crohn’s

In rare cases, Crohn’s disease can be caused by genetic variants that affect how the immune system regulates inflammation, including pathways involving tumor necrosis factor (anti-TNF drugs are commonly used to treat IBD).

In 2019, the Muise lab began work by targeting the BIRC3 gene, which is known to encode a protein linked to the TNF pathway. Despite disruptions caused by the COVID-19 pandemic, researchers were able to prove within two years that BIRC3 variants could cause Crohn’s at the cellular level.

From there, Muise built an international collaboration that united scientists in Canada, China, the U.S., Germany, Japan, France, Saudi Arabia and Spain. The group helped identify 14 Crohn’s patients from 10 families who carried BIRC3 variants—an unexpectedly high number for such a rare genetic cause.

Meanwhile, Muise’s team developed mouse and zebrafish models to analyze how these genetic variations drive gut inflammation. They discovered that BIRC3 was causing disease in all 14 patients. In the lab, they uncovered how: It disrupted a TNF pathway known as RIPK1.

“This is the first time BIRC3 variants have been identified as a genetic cause of Crohn’s disease,” says first author Qi Li, senior research associate in the Muise Lab. “Normally, BIRC3 protects cells in the intestine, but in all 14 patients they lost this function, making the gut more vulnerable to damage and raising the risk of Crohn’s disease.”

A new path toward precision medicine

Ryusuke Nambu, co-first author and former SickKids postdoctoral fellow, says this discovery will expand what is known about “monogenic” IBD (caused by changes in a single gene).

“Until now, research on monogenic IBD has mainly focused on very early-onset IBD, generally in children younger than 6,” says Nambu, who is now director of the Pediatric IBD Center at Japan’s Saitama Children’s Medical Center. “Yet our study suggests that some adult-onset patients, or those with a family history of IBD, may also carry genetic changes that are influencing their disease. This means that monogenic IBD could be far more widespread than we previously thought.”

Importantly, the team uncovered evidence suggesting the same RIPK1 pathway may play a role in other, more common forms of Crohn’s disease, not only in rare cases, supporting its potential as a therapeutic target.

“This is a very common pathway, which means we could potentially help a large number of patients with Crohn’s disease,” Muise says. “We can also use our findings to better understand who is likely to respond well to anti-TNF therapy and who will not, which is a brand-new finding.”

A drug designed to inhibit RIPK1 is currently being tested in clinical trials, which Muise says raises the possibility that patients could eventually be prescribed therapies based on the biological drivers of their disease.

“This is the promise of Precision Child Health coming into focus, our movement at SickKids to individualize care tailored to each unique patient,” Muise says. “Instead of relying on IBD therapies that suppress the entire immune system, we can block a specific pathway that is causing inflammation and bring effective, personalized treatments sooner for patients.”

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