Researchers have discovered a key driver of inflammatory bowel disease (IBD) and many other autoimmune diseases that affect the spine, liver and arteries, giving hope to millions of people around the world.
The discovery is exciting because the newly discovered biological pathway can be treated with drugs that are already being used to treat IBD and other diseases.
“What we found is one of the most central ways people go wrong when they get bowel disease, and it’s a sacred thing,” said Dr. James Lee, leader of the genetic mechanisms group at the Francis Disease Laboratory. Crick Institute in London.
“Even for pure and basic immunology, this is a really exciting discovery,” Lee added. But to show that this is uncontrolled in people with the disease tells us that not only do we have a better understanding of the disease, but it is something we can treat.
More than half a million people in the UK are affected, and at least 7 million people worldwide are affected, with the two main types being Crohn’s disease and ulcerative colitis. They arise when the immune system attacks the gut, causing debilitating symptoms ranging from abdominal pain and weight loss to diarrhea and blood in the stool. Although medications such as steroids can ease the symptoms, some patients require surgery to remove part of the colon.
Lee’s research team “stumbled upon” the discovery after examining a “gene desert,” a stretch of DNA on chromosome 21 that doesn’t code for proteins previously linked to IBD and other autoimmune diseases. Writing in NatureThey describe how they found a segment of DNA that appears to be a volume control for nearby genes. This “enhancer” appears only in immune cells called macrophages, and it increases a gene called ETS2 and increases the risk of IBD.
Through gene editing experiments, scientists have shown that ETS2 is central to the inflammatory behavior of macrophages and their ability to damage the gut in IBD. Lee, a consultant gastroenterologist at the Royal Free Hospital and UCLL, said: “The central drivers of this pathogenic process have been sought for some time, and this is what we stumbled upon.
The same biological pathway is thought to drive other body diseases, including ankylosing spondylitis, which causes inflammation of the spine and joints in about one in 1,000 people worldwide.
While there are no drugs that specifically target the ETS2 gene, scientists have identified anti-cancer drugs called MEK inhibitors that they suspect can suppress 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, scientists are working to adapt the drug so it only targets the patient’s macrophages. This is done by creating a “conjugate” in which the drug molecule is attached to a synthetic antibody that binds only to the target cells. “It’s much safer because it’s so targeted and you can use a lower dose,” Lee said. “We’ve already prepared the antibodies, I just have them sitting in my fridge.”
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Clinical trials are still needed to see if the combined drug can reduce IBD and other autoimmune conditions, but since MEK inhibitors are already used in cancer patients, researchers hope the process could be quick and 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 ancient people. “It has been conserved throughout evolutionary history because it is important in early bacterial responses,” Lee said. “So you don’t want to destroy it all together. You just need to reduce the movement by 50% and that effect can be enough.
Ruth Wakeman, from Crohn’s and Colitis UK, said: “Crohn’s and colitis are complex and lifelong conditions with no cure. However, such research is helping to answer some of the big questions that underlie them. This research is an exciting step towards a world free of Crohn’s and Colitis.