INDIANAPOLIS — Indiana University School of Medicine scientists have uncovered new evidence that an age-related blood condition may contribute to inflammatory bowel disease (IBD). Their findings suggest that a new drug strategy targeting the blood condition may reduce IBD severity and offers a new path for treating chronic diseases like Crohn’s disease and ulcerative colitis.

The blood condition, known as clonal hematopoiesis of indeterminate potential (CHIP), occurs when blood stem cells develop genetic mutations. The condition is common among older adults and is correlated with an increased risk of blood cancers, kidney disease and cardiovascular disease. In the study recently published in Blood¹, the researchers identified a definitive link between CHIP and the severity of gut inflammation.

"Our research identifies a new therapeutic target that sits at the intersection of aging, blood biology and chronic inflammation," said Reuben Kapur, PhD, director of the Herman B Wells Center for Pediatric Research and co-author on the study. "We found that these mutant blood cells in CHIP 'supercharge' inflammation in the gut, but more importantly, we discovered that targeting this pathway dramatically reduced damage and normalized how the immune system behaves."

According to the Centers for Disease Control, an estimated 2.4 to 3.1 million people have IBD in the United States, with prevalence highest in adults 45 and older. By analyzing data from the UK Biobank and the National Institutes of Health's All of Us Research Program, the IU team found that people with CHIP, specifically women and those with DNMT3A gene mutations, face a significantly higher risk of developing Crohn’s disease. They also noted that younger individuals with large TET2 gene mutations had an increased risk of ulcerative colitis.

Using mouse models, the researchers observed that blood stem cells carrying CHIP mutations led to more severe tissue damage and immune-cell buildup in the colon. They identified the APE1/Ref-1 inflammation pathway as a primary driver of this result. By using a drug called APX3330 to block that pathway, the scientists successfully reduced inflammation and restored colon health in their models. 

"Our most exciting discovery was that a single, oral drug that’s already known to be safe in humans could reverse nearly all of the harmful effects of CHIP-driven inflammation," said Ramesh Kumar, PhD, assistant research professor of pediatrics at the IU School of Medicine and lead author of the study. "This also suggests that even though CHIP mutations are age-related and previously thought to be untreatable, their harmful effects on inflammation may actually be reversible."

The use of APX3330, which was developed by IU scientist Mark Kelley, PhD, could become a non-immunosuppressive treatment option for IBD, which is a major development from current treatments that can weaken the immune system. Additionally, because CHIP contributes to inflammation in many conditions, this strategy may help improve other chronic diseases linked to aging.

The research team is now preparing for a Phase Ib clinical trial to test APX3330 in human IBD patients. They also plan to explore whether the drug could help reduce inflammation in other age-related conditions such as heart and kidney disease.

Kumar and Kapur are also researchers in the Wells Center's Hematologic Malignancies and Stem Cell Biology Program and the IU Melvin and Bren Simon Comprehensive Cancer Center.

IU School of Medicine’s Rahul Kanumuri, Baskar Ramdas, Santhosh Kumar Pasupuleti, Lakshmi Reddy Palam, Xuepeng Wang, Kanaka Sai Ram Padam and Mark Kelley are co-authors on the study. Additional authors include Linke Li, Sarah Urbut, Mesbah Uddin, Abhishek Niroula, Pradeep Natarajan and Zhi Yu from the Broad Institute of Harvard and MIT.

Reference:

1) https://ashpublications.org/blood/article-abstract/doi/10.1182/blood.2025032339/566854/Inflammatory-Bowel-Disease-induced-Inflammation

(Newswise/HG)