Researchers discover genetic cause of bowel diseases

Genomics

Researchers have discovered a new biological pathway in inflammatory bowel disease (IBD) and related conditions that can be targeted using existing drugs.

About 5% of the world’s population are currently affected by an autoimmune disease, such as IBD, the umbrella term for Crohn’s disease and ulcerative colitis.

These diseases are also becoming more common, with over half a million people living with IBD in the UK as of 2022, nearly double the 300,000 previously estimated.

Despite increasing prevalence, current treatments do not work in every patient and attempts to develop new drugs often fail due to an incomplete understanding of what causes IBD.

In research published in Nature today, scientists at the Crick journeyed into a ‘gene desert’ – an area of DNA that doesn’t code for proteins – which has previously been linked to IBD and several other autoimmune diseases.

They found that this gene desert contains an enhancer that was only active in macrophages and boosted a gene called ETS2, with higher levels correlating with a higher risk of disease.

Using genetic editing, the scientists showed that ETS2 was essential for almost all inflammatory functions in macrophages, including several that directly contribute to tissue damage in IBD. Simply increasing the amount of ETS2 in resting macrophages turned them into inflammatory cells that closely resembled those from IBD patients.

The team also discovered that many other genes previously linked to IBD are part of the ETS2 pathway, providing further evidence that it is a major cause of IBD.

Existing drugs to target IBD

The team found that MEK inhibitors, drugs already prescribed for other non-inflammatory conditions, were predicted to switch off the inflammatory effects of ETS2. They discovered that these drugs not only reduced inflammation in macrophages, but also in gut samples from patients with IBD.

The researchers are now working with LifeArc to find ways to deliver MEK inhibitors directly to macrophages.

James Lee, Group Leader of the Genetic Mechanisms of Disease Laboratory at the Crick, and Consultant Gastroenterologist at the Royal Free Hospital and UCL, who led the research, said: “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.”

Diana Spencer, Senior Digital Content Editor, DDW

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