Drug-targetable driver of inflammatory bowel disease discovered

Researchers in the UK have discovered a biological pathway that plays a major role in driving inflammatory bowel disease (IBD) and can be targeted using existing drugs.

The new study in Nature identified a gene called ETS2 is essential for inflammatory functions in macrophages – a type of immune cell important in IBD.

ETS2 can be blocked using drugs  which are already prescribed for other non-inflammatory conditions, and they result in reduced inflammation.

IBD is an umbrella term for chronic autoimmune conditions, Crohn’s disease and ulcerative colitis, which are becoming increasingly prevalent worldwide. These are complex, lifelong conditions that have no cure and for which current treatments are not always effective.

Lead researcher James Lee, a clinician-scientist and group leader in the Genetic Mechanisms of Disease Laboratory at the Frances Crick Institute, says better treatments are urgently needed.

“IBD usually develops in young people and can cause severe symptoms that disrupt education, relationships, family life and employment.

“Using genetics as a starting point, we’ve uncovered a pathway that appears to play a major role in IBD and other inflammatory diseases.

“Excitingly, we’ve shown that this can be targeted therapeutically, and we’re now working on how to ensure this approach is safe and effective for treating people in the future.”

The researchers identified ETS2 by investigating a “gene desert” – an area of DNA that doesn’t code for proteins – that had previously been linked to IBD.

They found a region of DNA called an enhancer that increases the output of a nearby gene, ETS2, but only in macrophages, the white blood cells which kill microorganisms, remove dead cells and stimulate the action of other immune system cells.

Using genetic editing, they showed that ETS2 was essential for almost all inflammatory functions in macrophages, including several that directly contribute to tissue damage in IBD.

They also showed that increasing the amount of ETS2 expression in resting macrophages turned them into inflammatory cells that closely resembled those from IBD patients.

Specific drugs that block ETS2 don’t exist so the team searched for drugs which might indirectly reduce its activity. They found that a group of cancer drugs called “MEK inhibitors” reduced inflammation in macrophages and in gut samples from patients with IBD.

Christina Stankey, a PhD student at the Crick and co-first author, says: “IBD and other autoimmune conditions are really complex, with multiple genetic and environmental risk factors, so to find one of the central pathways, and show how this can be switched off with an existing drug, is a massive step forward.”

As MEK inhibitors can have side effects in other organs, the researchers are now working to find ways to deliver them directly to macrophages.

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