Bowel disease breakthrough as researchers make ‘holy grail’ discovery | Digestive disorders

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 around the world.

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

“What we’ve discovered is one of the most central pathways that gets triggered when people get inflammatory bowel disease and it’s been somewhat of a holy grail,” said Dr. James Lee, head of group of the laboratory of genetic mechanisms of diseases at Francis. Crick Institute in London.

Lee added: “Even for pure, basic immunology, this is a really exciting discovery. But showing that this phenomenon is dysregulated in people with the disease not only gives us a better understanding of the disease, but also tells us that it’s something we can treat.

In the UK, more than half a million people suffer from inflammatory bowel disease, the two main forms of which are Crohn’s disease and ulcerative colitis, and at least 7 million people are affected in the world. They occur when the immune system attacks the gut, causing a range of debilitating symptoms from abdominal pain and weight loss to diarrhea and blood in the stool. Although medications such as steroids can relieve symptoms, some patients require surgery to remove part of their intestine.

Lee’s research team “stumbled upon” this discovery after studying a “genetic desert,” a portion of DNA on chromosome 21 that does not code for proteins, which has previously been associated with IBD and other autoimmune diseases. In Nature, they describe how they found a section of DNA that behaves as a volume control for nearby genes. This “enhancer” was only seen in immune cells called macrophages, where it stimulated a gene called ETS2 and increased the risk of IBD.

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

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

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

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

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Clinical trials are still needed to see if the right drug reduces IBD and other autoimmune diseases, but since MEK inhibitors are already used in cancer patients, researchers hope this process can be rapid and potentially completed within five years.

In subsequent work, scientists discovered that the ETS2 gene is at least half a million years old and was carried by Neanderthals and other archaic humans. “It has been preserved throughout evolutionary history, probably because it plays an important role in early bacterial responses,” Lee said. “So you wouldn’t want to destroy everything in one go. It is enough to reduce its activity by 50% and the effect could be sufficient.

Ruth Wakeman from Crohn’s and Colitis UK said: “Crohn’s disease and colitis are complex, lifelong conditions for which there is no cure, but research like this helps us answer some questions. big questions about their causes. This research is a truly exciting step toward the possibility of a world free of Crohn’s disease and colitis.

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