Layilin prevents unwanted clotting by tamping down the activity of a clot-triggering molecule called Rac1. In mice without the layilin gene-and in people with IBD-Rac1 is always a little bit too active, which means platelets are too prone to forming clots.
But there’s good news. Drugs that prevent Rac1 activity are already in clinical trials for other conditions, and the researchers’ results suggest that these Rac1 inhibitors could be powerful therapeutics for IBD.
One Rac1 inhibitor reduced excessive clotting in human platelets in a dish. The inhibitor also decreased the level of tissue damage in the gut in a mouse model of IBD.
Promisingly, the drug decreased clotting in platelets from IBD patients even more strongly than it affected healthy cells. “We have shown a hyperactivation pathway in resting IBD patient platelets, but they’re also incredibly sensitive to treatment, moreso than those from a healthy person,” Mellema says.
Normalizing Rac1 activity might not only reduce the risk of heart attack and stroke-it could also help alleviate day-to-day IBD symptoms, the researchers say. Excessive clotting can block blood flow in the gut and make inflammation worse, which means that preventing clotting could reduce inflammation.
Unlike established anti-clotting drugs, the researchers say, Rac1 inhibitors shouldn’t lead to an increased risk of dangerous bleeding, which is a serious concern for IBD patients with chronic inflammation. Blocking Rac1 won’t interfere with other, independent pathways that can trigger platelet clotting, so the cells should still be able to form needed clots in response to injury.
“We’re targeting a pathway that is not pre-activated in healthy people,” Petrey says. “So we can address that step of the pathway, and if there’s a significant injury, the platelets can overcome that inhibition.”
Other groups had been looking into the potential of Rac1 inhibitors to reduce inflammation in IBD. The new work emphasizes the potential of these drugs to address multiple symptoms. “Paying more attention to what we can do to address these blood clotting risks could significantly improve patient lives,” Petrey says.