Current treatments for inflammatory bowel disease (IBD) can help manage the disease’s effects, but improved treatments are desperately needed. To develop those treatments, it’s important to understand the underlying biological causes that drive different forms of IBD, including Crohn’s disease and ulcerative colitis.
Scott B. Snapper, MD, PhD, a physician-scientist in the Crohn’s and Colitis Center within the Division of Gastroenterology, Hepatology and Endoscopy at Brigham and Women’s Hospital, has devoted his research to this topic—both in the lab and the clinic. His current work focuses on determining the causes of IBD and employing novel animal models as well as direct human studies, including early-stage clinical trials, to study it.
“Since I began my research career, my goal has always been to better understand these diseases,” says Dr. Snapper, who trained as a microbiologist and immunologist in addition to training as a gastroenterologist. “All of that work has been leading up to developing new therapeutics.”
Mouse Models Reveal Disease Mechanisms
When Dr. Snapper started his research, there was a need for better animal models for studying IBD. One reason was that most cases of IBD are caused by numerous genetic factors. He realized that by studying the rare cases caused by single genes, he could pull apart the mechanisms that contribute to these conditions in more common cases as well.
“We use these rare examples to help us understand the cellular and molecular mechanisms and the host-microbial interactions that occur in all people who get Crohn’s disease and ulcerative colitis,” he says.
The first mouse model he worked with was one for Wiskott-Aldrich syndrome, a rare monogenic disease characterized by abnormal immune system function, among other issues. All the mice with the disease developed IBD. Today, there are more than 60 mouse models for studying different forms of IBD.
The Snapper Laboratory employs a number of basic, translational and clinical research strategies to understand and define not only the constituents but also the mechanisms that regulate intestinal homeostasis as it pertains to gastrointestinal health and IBD. Among the ongoing projects in his lab are the study of intestinal epithelial cells, immune cells and cytokines as well as translational work using humanized mice. This research is laying the foundation for the development of clinical trials.
Decoding the Underlying Causes of IBD
Among the findings that have come out of Dr. Snapper’s lab are that some cases of IBD presenting in very young children are caused by the absence of the interleukin-10 receptor.
“Patients lacking this receptor make a lot of the cytokine interleukin-1,” says Dr. Snapper, who is also chief of the Division of Gastroenterology, Hepatology and Nutrition and director of the Inflammatory Bowel Disease Center at Boston Children’s Hospital. “We’ve shown in early studies that in these patients, you can ameliorate much of their disease by blocking interleukin-1.”
Dr. Snapper says that this treatment has served as a bridge to offering bone marrow transplants for children with this rare immunodeficiency syndrome. He also notes ongoing efforts to identify subsets of all IBD patients with an enhanced interleukin-1 signature who might benefit from IL-1 blockade.
Research employing several mouse models of IBD, including the murine model of the Wiskott-Aldrich syndrome, has revealed another underlying mechanism of IBD, this one related to regulatory T cells.
“We’ve found in a novel humanized mouse model of IBD that you can expand regulatory T cells by giving low doses of interleukin-2 and improve disease,” Dr. Snapper says. This work has been used for treating graft-versus-host disease in patients who have undergone bone marrow transplants, but studies in mice suggest it could be an effective treatment for IBD as well.
Applying Lab Findings to Clinical Trials
At the 2021 Digestive Disease Week conference, Dr. Snapper and Brigham colleagues including Jessica R. Allegretti, MD, MPH, Vanessa Mitsialis, MD, Matthew J. Hamilton, MD, and Joshua R. Korzenik, MD, presented the results from an open-label, single-arm, phase 1b/2a trial that looked at whether subcutaneously administered, low-dose interleukin-2 is safe and results in a biological response. The study, which enrolled 26 patients with ulcerative colitis, showed that this treatment was well-tolerated, and was associated with a biological response and the expansion of regulatory T cells in patients with moderate to severely active ulcerative colitis.
“This treatment led to clinical improvement in more than 50% of the patients and complete remission in about a quarter of them,” Dr. Snapper says. “These are patients who had already failed multiple drugs.”
A new early-stage study has enrolled eight patients to look at whether expanding regulatory T cells with interleukin-2 can provide the same benefit in people with Crohn’s disease.
Outside of his clinical trials, Dr. Snapper was instrumental in establishing the Very Early Onset Inflammatory Bowel Disease (VEO-IBD) Consortium, an international group of investigators studying IBD in young children. The group includes scientists from North America, Europe, Australia, South America, Israel and the Middle East who are all focused on these efforts.
The VEO-IBD Consortium has identified numerous genetic defects that cause IBD and has developed novel therapeutic approaches. The group has received support from a number of philanthropies, including the Helmsley Charitable Trust and the National Institutes of Health, as well as support from the pharmaceutical and biotechnology industries.