An Oral Answer to IBD

A new study of mice and lab-grown human colon “organoids” indicates that an experimental drug developed by Johns Hopkins Medicine researchers can substantially reduce symptoms of inflammatory bowel disease (IBD) in preclinical models.

The experimental drug, given orally, inhibits a gut enzyme that is overproduced in people and in animal models of IBD, a disorder estimated to afflict more than 3 million adult Americans. A report on the new study was published in Science Translational Medicine.

IBD, a disease category that includes Crohn’s disease and ulcerative colitis, is an autoimmune disorder marked by immune system cells that overreact and attack healthy tissue. The process results in chronic inflammation of the gut, abdominal pain, diarrhea, weight loss and rectal bleeding. Current treatments rely mostly on anti-inflammatory drugs, such as steroids, along with other immune system suppressors, diet and lifestyle changes, or surgery to remove or bypass diseased intestinal tissue. However, many people with IBD experience debilitating symptoms even with treatment.

“There is a huge need to develop new therapies for IBD patients because about 40% are not benefiting from current treatments,” says neurologist Barbara Slusher, director of Johns Hopkins Drug Discovery, the study’s senior and corresponding author. “The idea that we’ve discovered a brand-new therapeutic target and successfully developed a well-tolerated and efficacious pill to inhibit the target is really exciting.”

Slusher explains that the activity of the target enzyme, gastrointestinal glutamate carboxypeptidase II (GCPII), is highly upregulated in patients with IBD compared to people without the disorder.

“Our new GCPII inhibitor drug was designed to be gut restricted, meaning it stays in the gut with minimal exposure to the rest of the body when given orally,” says Rana Rais, director of drug metabolism and pharmacokinetics for Johns Hopkins Drug Discovery. “This targets gastrointestinal GCPII while limiting systemic side effects.”

In the new studies, the experimental GCPII-inhibiting drug Slusher and her team developed was tested in two mouse models of colitis. Results showed that the drug blocked about 75% of the colon GCPII activity. As a result, the treated animals showed improved stool consistency, less rectal bleeding and decreased colon inflammation, with no apparent adverse side effects. The drug also showed protective results when tested in a human colon organoid injury model grown from patient biopsy tissues.

“This is the first demonstration of an oral GCPII inhibitor protecting gut function,” says Diane Peters, assistant professor of pharmacology and molecular sciences and first author of the study.