June 21, 2024

Researchers have discovered a major driver of inflammatory bowel disease (IBD) and several other immune disorders that affect the spine, liver and arteries, raising hope for millions of people worldwide.

The breakthrough is particularly exciting because the newly discovered biological pathway can be targeted by drugs already in use, with work underway to adapt them to patients with IBD and other conditions.

“What we found is one of the many central pathways that goes wrong when people get inflammatory bowel disease and it was something of a holy grail,” said Dr James Lee, group leader of the Genetic Mechanisms of Disease Laboratory at the Francis Crick Institute in London.

Lee added: “Even for pure, fundamental immunology, this is a very exciting discovery. But to show that it is dysregulated in people who get disease not only gives us a better understanding of the disease, it tells us that it’s something we can treat.”

More than half a million people in the UK have inflammatory bowel disease, the two main forms of which are Crohn’s disease and ulcerative colitis, with at least 7 million affected worldwide. They occur when the immune system attacks the intestines, causing a variety of debilitating symptoms from abdominal pain and weight loss to diarrhea and blood in the stool. While medicines such as steroids can relieve the symptoms, some patients require surgery to remove part of their intestines.

Lee’s research team “stumbled upon” the discovery after examining a “gene desert,” a stretch of DNA on chromosome 21 that does not code for proteins, which has previously been linked to IBD and other autoimmune diseases. Write in Earth, they describe how they found a section of DNA that acts like a volume control for nearby genes. This “enhancer” was only seen in immune cells called macrophages, where it amplified a gene called ETS2 and increased the risk of IBD.

Through gene editing experiments, the scientists showed that ETS2 is central to the inflammatory behavior of macrophages and their ability to damage the gut in IBD. “There has been a search for some time for the central drivers of this pathogenic process, and this is what we stumbled upon,” says Lee, who is also a consultant gastroenterologist at the Royal Free Hospital and UCL.

The same biological pathway is thought to drive other autoimmune disorders, including ankylosing spondylitis, which causes spine and joint inflammation in about one in 1,000 people worldwide, and rarer autoimmune diseases that affect the liver and arteries.

Although there are no drugs that specifically target the ETS2 gene, the scientists have identified a class of anticancer drugs called MEK inhibitors that they suspect would dampen the gene’s activity. In laboratory tests, the drugs performed as expected, reducing inflammation in intestinal samples from patients with IBD.

Because MEK inhibitors have side effects in other organs, the scientists began working to modify the medicine so that it only targets a patient’s macrophages. This is done by creating a “conjugate” where the drug molecule is attached to a synthetic antibody that only binds to the target cells. “It’s safer because it’s more targeted and you can use a lower dose,” Lee said. “We already developed the antibody conjugate, I have it in my freezer.”

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Clinical trials are still needed to see if the modified drug reduces IBD and other autoimmune conditions, but because MEK inhibitors are already used in cancer patients, researchers hope the process can be completed quickly and possibly within five years.

In further work, the scientists found that the ETS2 gene is at least half a million years old and was carried by Neanderthals and other archaic humans. “It’s been conserved over evolutionary history, probably because it’s important in early bacterial responses,” Lee said. “So you wouldn’t want to knock everything out together. You only need to turn down its activity by 50% and its effect can be enough.”

Ruth Wakeman at Crohn’s and Colitis UK said: “Crohn’s and colitis are complex, lifelong conditions for which there is no cure, but research like this is helping us to answer some of the big questions about what causes it. This research is a very exciting step towards the possibility of a world free of Crohn’s and colitis.

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