For many individuals with inflammatory bowel disease, treatments that target inflammation directly don’t work. Now, new research suggests that a promising alternative could be to block a protein involved in blood clotting.
Scientists at the Washington University School of Medicine in St. Louis, MO, found that those with the most extreme symptoms often had higher involvement in genes associated with blood clotting, after analyzing genetic evidence from many people with inflammatory bowel disease ( IBD).
Both the inflammatory cells and the epithelial cells, or the cells of the gut lining, had active genes in common.
The SERPINE-1 and PAI-1 genes, which are the proteins they encode, were particularly active, so the team decided to concentrate on them.
The early stages of blood clotting involve both PAI-1 and its encoding gene, but the latest study is the first to link them, albeit indirectly, to inflammation.
The researchers found that, in a mouse model of the disease, an experimental drug that blocked PAI-1 alleviated the symptoms of IBD.
A detailed account of the study is now provided in the journal Science Translational Medicine.
“Senior study author Thaddeus S. Stappenbeck, Ph.D., a professor of laboratory and genomic medicine, says,” No one has ever thought of targeting something like this.
“But,” he adds, “we have discovered something here that could help many people with IBD, especially those who do not benefit much from current therapies.”
Ulcerative colitis and Crohn’s disease
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, according to 2015 data from the Centers for Disease Control and Prevention ( CDC).
The main difference between ulcerative colitis and Crohn ‘s disease is that the inflammation largely affects the colon in ulcerative colitis, whereas it can occur anywhere in the gastrointestinal tract in Crohn’s disease.
IBD symptoms mainly consist of abdominal pain , diarrhea, weight loss , and fatigue. Those with more serious diseases can also be affected by rectal bleeding and bloody stools.
The standard treatment is the administration of corticosteroids or other inflammation suppressant drugs. For many individuals with IBD, however, this either does not work or gives only slight relief.
With strong drugs that suppress the immune system, including those that block the immune protein TNF, doctors can also treat more severe symptoms. It can relieve symptoms, but it doesn’t always work, and can also increase the risk of cancer and infection.
Researchers took a new direction
Prof. Stappenbeck and his team decided to go in a different direction, instead of following the already well-trodden path of searching for drugs that target inflammation.
Through routes that are not directly related to inflammation, they carried out a detailed search for genes that could contribute to IBD. They analyzed genetic data from 1,800 biopsy samples of individuals with IBD to do this.
The data was generated by various studies comparing the biopsies of individuals with IBD with those without IBD. Samples from inflamed and non-inflamed gut tissue and from cases of severe, moderate, and mild illness were included in the biopsies of people with IBD.
It was this analysis that produced a list of genes that are more active in individuals with IBD, all involved in blood clotting.
The finding supports what others have observed: that individuals with IBD are more than twice as likely to develop blood clotting issues as those without IBD, especially during flare-ups.
The team eventually honed the list to concentrate on SERPINE-1 and its PAI-1 protein, noting their high level of inflammatory and epithelial cell activity and the fact that they were both involved in the early stages of blood clotting.
“What is most exciting here,” says Prof. Stappenbeck, “is that SERPINE-1 and its protein appear to be most highly expressed in people with the most severe disease and those who do not respond to biologics that are immunosuppressive.”
Noninflammatory target looks promising
By giving mice a compound that produces the same damage and symptoms in the gut, he and his colleagues then developed a mouse model of IBD.
The IBD mice lost weight, and their gut tissue displayed lesions and elevated levels of inflammatory proteins and cells consistent with signs of IBD, relative to control mice that the team had treated with a harmless compound.
Furthermore, the expression of SERPINE-1 was six times higher in the gut tissue of the IBD mice than that of the control mice.
Some of the IBD mice were then treated by the team with MDI-2268, an experimental drug that blocked the action of PAI-1, and the remainder with a placebo.
The IBD mice that obtained the experimental drug started to exhibit signs of better health compared with those that received placebo. Their weight loss decreased, and fewer lesions and reduced inflammation were seen in their gut tissue.
“We found a specific target that is not an inflammatory molecule, and yet blocking it decreases inflammation and signs of disease, at least in mice,” Prof. Stappenbeck states, adding, “If more research shows our results, we conclude that this target may be useful for a higher number of patients.”
The team indicates that for individuals with IBD who find no relief from those currently available, the finding will lead to new types of treatment.
“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.
