If the direct approach reaches a roadblock, consider a detour. That’s the kind of thinking that may lead to more roundabout—and potentially more effective—treatments for inflammatory bowel disease (IBD). In IBD, the usual approach is to directly target inflammation. Unfortunately, this approach fails many patients, who suffer frequent episodes of abdominal pain diarrhea, and in severe cases, rectal bleeding. Another approach—an indirect approach—would involve tamping down a gene, SERPINE-1, that is best known for its role in blood coagulation.
This gene, which encodes the protein plasminogen activator inhibitor-1 (PAI-1), has been found to be highly expressed in aggressive cases of IBD. PAI-1 also appears to promote inflammation indirectly by targeting another protein, tissue plasminogen activator (tPA), which helps regulate intestinal inflammation.
These findings emerged from a global transcriptomic analysis conducted by scientists based at the Washington University School of Medicine in St. Louis. The analysis, which uncovered gene expression patterns in tissues obtained from colon biopsies, enabled the scientists to identify noninflammatory IBD-related pathways. The coagulation gene pathway, the scientists determined, was among the most enriched gene sets in patients with IBD. Also, one gene stood out: SERPINE-1.
To verify the role of the gene and its protein in gut inflammation, the researchers gave mice a chemical that causes gut inflammation similar to IBD, or a harmless chemical for comparison. The mice that received the damaging chemical lost weight, their intestines had signs of injury with many inflammatory cells and proteins, and the SERPINE-1 gene was expressed six times higher than in mice that received the harmless chemical.
When the mice with IBD-like symptoms were treated with a compound called MDI-2268 that blocked the activity of the protein, they fared much better. They lost less weight, and their intestines showed less destruction and inflammation than mice that were treated with a placebo.
Detailed findings appeared March 6 in the journal Science Translational Medicine, in an article entitled, “PAI-1 augments mucosal damage in colitis.”
“Using [a] gene-network analysis across 14 independent cohorts and 1800 intestinal biopsies, we found that, among the coagulation pathway genes, plasminogen activator inhibitor-1 (PAI-1) expression was highly enriched in active disease and in patients with IBD who did not respond to anti-TNF biologic therapy and that PAI-1 is a key link between the epithelium and inflammation,” wrote the article’s authors. “Intestinal epithelial cells produced tPA, which was protective against chemical and mechanical-mediated colonic injury in mice. In contrast, PAI-1 exacerbated mucosal damage by blocking tPA-mediated cleavage and activation of anti-inflammatory TGF-β, whereas the inhibition of PAI-1 reduced both mucosal damage and inflammation.”
“There’s a lot of interest in novel therapeutic approaches for IBD because inhibiting inflammatory molecules doesn’t work for all patients,” said senior author Thaddeus S. Stappenbeck, MD, PhD, the Conan Professor of Laboratory and Genomic Medicine. “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. If further research bears out our findings, we think this target could be helpful to a greater number of patients.”
More than 1 million people in the United States have IBD, which includes Crohn’s disease and ulcerative colitis. Both conditions are marked by out-of-control inflammation but in different parts of the gastrointestinal tract. They typically are treated first with general anti-inflammatory drugs such as corticosteroids. In more severe cases, people are given more potent immune suppressors such as TNF inhibitors, which neutralize an important immune protein. TNF inhibitors are sold under brand names such as Humira and Remicade. Immunosuppressants can be very effective, but they do have side effects such as increased risk of infection and cancer.
While researchers have focused countless hours on finding drugs to dampen IBD patients’ unruly immune systems, there are other untapped sources for therapies of the disease – such as the behavior of the epithelial cells that line the gut. Stappenbeck and first author Gerard Kaiko, PhD, a former postdoctoral researcher in Stappenbeck’s lab who is now at the University of Newcastle in Australia, realized that overlooked aspects of IBD might be a rich source of new drug targets.
“What’s most exciting here 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,” Stappenbeck said. “No one’s ever thought of targeting something like this. But here we’ve found something that might help lots of people with IBD, especially the ones who aren’t benefiting much from current therapies.”