Treatments that target inflammation directly don't work for many people with inflammatory bowel disease. Now, new research suggests that blocking a protein involved in blood clotting could be a promising alternative.
After studying genetic data from lots of people with inflammatory bowel disease (IBD), scientists at the Washington University School of Medicine in St. Louis, MO, found that those with the most severe symptoms also had higher activity in genes associated with blood clotting.
The active genes were common to both the inflammatory cells and the epithelial cells, or the cells of the gut lining.
The gene SERPINE-1 and PAI-1, which is the protein that it encodes, were particularly active, so the team decided to focus on them.
Both PAI-1 and its encoding gene are involved in the early stages of blood clotting, but the recent study is the first to link them to inflammation, albeit indirectly.
The researchers found that an experimental drug that blocked PAI-1 alleviated the symptoms of IBD in a mouse model of the disease.
The journal Science Translational Medicine now features a detailed account of the study.
"No one's ever thought of targeting something like this," says senior study author Thaddeus S. Stappenbeck, Ph.D., a professor of laboratory and genomic medicine.
"But," he adds, "here we've found something that might help lots of people with IBD, especially the ones who aren't benefiting much from current therapies."
Ulcerative colitis and Crohn's disease
According to 2015 data from the Centers for Disease Control and Prevention (CDC), around 3 million adults in the United States have reported receiving a diagnosis of either ulcerative colitis or Crohn's disease, the two conditions that make up IBD.
The main difference between ulcerative colitis and Crohn's disease is that in ulcerative colitis, the inflammation largely affects the colon, whereas in Crohn's disease, it can occur anywhere in the gastrointestinal tract.
The standard treatment is to administer corticosteroids or other drugs to suppress the inflammation. However, for many people with IBD, this either does not work or only gives slight relief.
Doctors can also treat more severe symptoms with strong drugs that suppress the immune system, including those that block the immune protein TNF. These can relieve symptoms, but they don't always work, and they can also raise the risk of cancer and infection.
Researchers took a new direction
Instead of following the already well-trodden path of searching for drugs that target inflammation, Prof. Stappenbeck and his team decided to go in a different direction.
They carried out a detailed search for genes that might contribute to IBD through routes that are not directly related to inflammation. To do this, they analyzed genetic data from 1,800 biopsy samples of people with IBD.
Various studies had generated the data by comparing the biopsies of people with IBD with those without IBD. The biopsies from people with IBD included samples from inflamed and noninflamed gut tissue and from cases of severe, moderate, and mild disease.
It was this analysis that produced a list of genes, all involved in blood clotting, that are more active in people with IBD.
The finding supports what others have observed: that people with IBD are more than twice as likely as those without IBD to develop blood clotting problems, especially during flare-ups.
Eventually, the team honed the list to focus on SERPINE-1 and its protein PAI-1, noting their high level of activity in both inflammatory and epithelial cells and the fact that they were both involved in the early phases of blood clotting.
"What's most exciting here," Prof. Stappenbeck remarks, "is that SERPINE-1 and its protein seems to be most highly expressed in people with the most severe disease and those who don't respond to immunosuppressive biologics."
Noninflammatory target looks promising
He and his colleagues then developed a mouse model of IBD by giving mice a compound that produces the same damage and symptoms in the gut.
Compared with control mice that the team had treated with a harmless compound, the IBD mice lost weight and their gut tissue showed lesions and high levels of inflammatory proteins and cells consistent with signs of IBD.
In addition, SERPINE-1 expression in the gut tissue of the IBD mice was six times higher than in that of the control mice.
The team then treated some of the IBD mice with MDI-2268, an experimental drug that blocked the action of PAI-1, and the rest with a placebo.
Compared with those that received placebo, the IBD mice that received the experimental drug began to show signs of improved health. Their weight loss diminished, and their gut tissue showed fewer lesions and reduced inflammation.
Prof. Stappenbeck explains, "We found a unique target that's not an inflammatory molecule, and yet blocking it reduces inflammation and signs of disease, at least in mice," adding, "If further research bears out our findings, we think this target could be helpful to a greater number of patients."
The team suggests that the finding will lead to new types of treatment for people with IBD who find no relief from those that are currently available.
"There's a lot of interest in novel therapeutic approaches for IBD because inhibiting inflammatory molecules doesn't work for all patients."
Thaddeus S. Stappenbeck, Ph.D.