Researchers make advances toward more effective IBD therapies

New regenerative medicine technique may repair and protect the colon

For millions of patients with Inflammatory Bowel Disease (IBD), clinical remission can seem out of reach. Current therapeutics like corticosteroids and biologics help manage symptoms and control chronic inflammation but do little to repair damage to the intestinal lining. Now, a new regenerative medicine technique is showing promise for both its ability to heal this tissue and potentially prevent relapse.

As reported in Advanced Science, Berkeley researchers have demonstrated that treatment with DPCA, an enzyme inhibitor molecule shown to trigger regeneration in mammals, can protect against and repair colon damage in a mouse model of colitis. This work, which builds off decades of research, suggests that short-term use of this small molecule drug could someday provide a restorative therapy for patients with IBD — and a path to remission.

A person holding onto their stomach with one hand.
Inflammatory Bowel Disease (IBD) can cause severe, chronic inflammation and pain. (Image by iStock)

“Through a combination of technology and biological inspiration, we’ve developed a potentially new therapeutic strategy for IBD,” said Phillip Messersmith, principal investigator of the study and professor of bioengineering and of materials science and engineering. “It utilizes an innovative drug delivery system developed at Berkeley and a key molecule in regeneration to preserve and restore barrier function in the colon.”

The new drug works by targeting the HIF-1α pathway, which prior research has shown helps regenerate damaged tissue. Ellen Heber-Katz, a co-author of this study and professor at Lankenau Institute for Medical Research, discovered years ago that increased HIF-1α expression following an injury plays a direct role in healing in mammals — something she uncovered after 20 years of studying the spontaneous regeneration of tissues in the Murphy Roths Large (MRL) laboratory mouse strain. Messersmith’s lab subsequently developed a delivery system for DPCA, a small molecule drug that can increase HIF-1α levels. To date, the researchers have demonstrated the drug’s ability to restore tissue loss in ear hole wounds and periodontitis in mice.

This latest study marks the first time that the drug has been shown to heal intestinal ulcers associated with IBD. “We hope that one day our therapy can be used in conjunction with current treatments or on its own to not only mitigate inflammation and manage symptoms but induce healing,” said Kelsey DeFrates, a Ph.D. student in bioengineering and biomedical engineering and the study’s lead author.

DeFrates notes that in regeneration — unlike normal mammalian healing — healthy tissue is completely replaced without any scarring. This distinction is particularly important for patients with IBD, whose severe lesions place them at risk of building up scar tissue, which can cause pain, impair organ function or limit movement. “If we can prevent scarring or the development of chronic wounds and strengthen the bowel tissue through regeneration, we might be able to prevent disease relapse,” said DeFrates.

In this study, the researchers initially investigated the drug’s protective effects against colitis. It proved to be effective at preventing the formation of intestinal lesions and associated weight loss in mice models. Researchers believe that the drug stabilized HIF-1α in the colon, which in turn helped increase mucus production and preserve barrier function.

They then tested DPCA’s effectiveness as a treatment after disease onset. The researchers found that one injection of the gel accelerated “re-epithelialization” of the colon as well as weight gain.

“Based on our results, we think that short-term administration of DPCA may someday serve as a restorative therapy for IBD,” said Messersmith. “Ultimately, we want to find a way to turn back the clock for IBD patients and regenerate that [damaged] tissue back to the native tissue.”

In addition to these findings, the researchers came across a surprising “scientific nugget,” according to Messersmith. “We found evidence of what we call an epithelial-to-mesenchymal transition in the intestinal tissues,” he said. “That’s interesting and potentially important because in primitive organisms, like axolotl, which can regenerate whole limbs, this transition is a characteristic of its regeneration strategy.”

More study is needed, but the researchers remain optimistic about the drug’s potential. “The idea is that, in the future, IBD patients will be able to go to their healthcare provider and get a shot in the arm, or maybe an oral version, of our drug,” said Messersmith. “And that could help place them on the road to remission.”

Other co-authors of this study include undergraduate bioengineering student Elaine Tong and postdoctoral researcher Jing Cheng, both in Messersmith’s lab.

This work was supported by the National Science Foundation Graduate Research Fellowship under Grant No. DGE 1752814; the National Institutes of Health Grant RO1DE021104 and the UC Berkeley Bakar Spark Fellows Award 2022.

Read this story on the Berkeley Engineering website.