Research News

Research from a collaboration between Cleveland Clinic's Lerner Research Institute, Johns Hopkins University School of Medicine and Johns Hopkins Drug Discovery is addressing the urgent need for new inflammatory bowel disease (IBD) therapies.

While better treatments have been developed for two major forms of IBD, Crohn's disease and ulcerative colitis, up to 40% of people with moderate-to-severe IBD do not adequately respond to existing drugs.

"We've reached a therapeutic ceiling in IBD treatments," says Christine McDonald, PhD, Department of Inflammation & Immunity at Cleveland Clinic's Lerner Research Institute. "While some people have initial success with a certain drug, they often lose responsiveness over time. So, if a patient is diagnosed in their teens and lives into their 80s, the initial drug regiment will likely have stopped being effective – requiring a change in therapy, dose escalation with more side effects or potentially surgical removal of intestine."

Collaborating to accelerate discovery

Dr. McDonald met Diane Peters, DVM, PhD, MS, assistant professor of pharmacology and molecular sciences at Johns Hopkins, at the GI Inflammatory Diseases Summit in 2019, and quickly recognized an opportunity to collaborate on moving the needle for new IBD therapies.

Initial discussions turned into a multidisciplinary collaboration, including the pharmacologic expertise of Barbara Slusher, PhD, MAS, Director of Johns Hopkins Drug Discovery, and Rana Rais, PhD, Director of Johns Hopkins Drug Metabolism and Pharmacokinetics. Their collaborative work highlighting a new class of oral inhibitors to the enzyme glutamate carboxypeptidase II (GCPII), was published in Science Translational Medicine.

GCPII is not normally detected in the ileum or colon, but it is overexpressed in Crohn's disease and ulcerative colitis. While previous evidence pointed to GCPII as a therapeutic target for IBD, the existing GCPII inhibitors were not suitable for clinical translation due to poor pharmaceutic properties and the potential to affect the normal functions of GCPII expressed in the nervous system. The challenge was to develop an oral GCPII inhibitor that would stay localized to the intestine and prove effective.

"When we discovered that GCPII was abundantly upregulated in the gastrointestinal epithelium of IBD patients, we became extremely curious about its function," says Dr. Peters. "We were eager to collaborate with Dr. McDonald, an expert in human epithelial barrier structure and function. This collaboration yielded positive results, and we're excited about next steps in our research working in tandem."

Together, the teams demonstrated that local inhibition of dysregulated gastrointestinal GCPII using the gut-restricted, orally delivered therapeutic agent (S)-IBD3540, reduces disease severity in acute preclinical colitis and is a promising approach for a new IBD therapeutic.

Currently, the John Hopkins labs are working to translate these recent findings into clinical trials. Next steps in the research will be to better understand the role of GCPII in the inflamed gut and validating the use of GCPII as a biomarker in IBD patient populations.

Data generated in the McDonald lab for this research was the work of András Ponti, who is currently a graduate student in the Cleveland Clinic Lerner College of Medicine Molecular Medicine PhD program. Many thanks are extended to the individuals who donated intestinal tissue for these studies.

This research was funded by the Crohn's and Colitis Foundation, CURE 4 IBD and the National Institutes of Health.