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New potential therapeutic target identified for Crohn’s disease

New research has shed light on how known genetic risk factors can contribute to Crohn’s disease and treatment response, opening the door to new treatment approaches. Crohn’s disease is a form of inflammatory bowel disease in which the digestive tract is marked by lesions of damaging inflammation. It can start at any age, causing lifelong episodes of cramping, diarrhea, and malnutrition. Medications that block a major component of the inflammatory response called tumor necrosis factor (TNF) are effective for many people, but in some cases the disease does not respond to these drugs. Among the scores of genetic variations that have been linked to a higher risk for developing Crohn’s disease, changes in a gene called NOD2 that impair its function have been found to be a major risk factor. Exactly how these NOD2 genetic variations could contribute to Crohn’s disease has been unclear, however, which has been a major roadblock for developing new therapies.

Researchers set out to answer this question by analyzing intestinal samples from a well-characterized group of male and female children with Crohn’s disease. They found that genetic variations inhibiting NOD2 function were linked to changes in fibroblasts (cells that make up connective tissue) and immune cells in Crohn’s disease lesions. Specifically, these cell types showed signs that they were “activated” and producing factors involved in inflammation. Importantly, activated immune cells and fibroblasts have also been found in lesions from people with refractory Crohn’s disease that is resistant to anti-TNF therapy, suggesting that these activated cells provide an additional route to inflammation that is independent of TNF-mediated inflammation. Using cultured cells and a zebrafish model that effectively mimics human Crohn’s disease, the researchers identified a protein known as gp130 that plays a critical role in activating these cells when NOD2 is impaired. Data from women and men with Crohn’s disease that did not respond well to anti-TNF therapy showed high levels of intestinal proteins in the cellular pathway used by gp130. Additionally, the researchers found that treating zebrafish or cultured cells with a gp130-blocking drug inhibits activation of inflammatory cells. More research is needed to determine if blocking gp130 will similarly reduce cellular activation in human intestinal lesions. However, this study suggests that drugs targeting gp130, when used in conjunction with anti-TNF therapy, might be effective treatments for people with Crohn’s disease resulting from NOD2 risk variants.

Nayar S, Morrison JK, Giri M,…Cho JH. A myeloid-stromal niche and gp130 rescue in NOD2-driven Crohn's disease. Nature 593: 275-281, 2021.

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