New technology improves efficacy of inflammatory bowel disease drugs

More Canadians suffer from inflammatory bowel disease (IBD) than anywhere else in the world, yet current treatments often have debilitating side effects and are not always effective.

According to Crohn's and Colitis Canada, 1 in 140 Canadians lives with Crohn's or colitis, the two main forms of IBD. The disease inflames the lining of the gastrointestinal (GI) tract and disrupt the body's ability to digest food, absorb nutrition, and eliminate waste in a healthy matter. This can lead to severe abdominal pain, chronic diarrhea, and life-threatening complications.

GlycoNet researchers from the University of British Columbia, BC Children's Hospital, and Agriculture and Agri-Food Canada, are challenging the status quo as they develop a technology that they termed "GlycoCage." This technology is aimed to improve the efficacy of IBD drugs by refining the method of drug delivery to patients.

IBD has a significant economic impact--in billions of dollars. Half of this comes from the direct costs associated with IBD treatment, where no definitive cure exists. The other half comes from the loss of productivity in those afflicted with the disease."

Dr. Harry Brumer, Study Lead Investigator and Professor, University of British Columbia

As a chronic disease, treatments options are rough. "For patients who resort to biologics--the last type of treatment when all others fail--they need to take the infusion every six weeks, and every time the treatment takes at least half a day," says Dr. Laura Sly, Co-Investigator of the project and Associate Professor at the BC Children's Hospital. "And some people still don't respond to the treatments."

Cage it or lose it

For other types of patients, IBD are often treated with orally administered anti-inflammatory drugs, but these can be absorbed by the stomach or small intestine before reaching the lower gastrointestinal (GI) tract--where the drugs are supposed to be.

This means in order to get a sufficient amount of drug to the target site, a higher initial dosage is needed to compensate its loss during the transit. In the case of steroid anti-inflammatory drugs, long-term systemic uptake could result in side effects like thinning bones, severe fatigue, or muscle weakness.

Brumer, a glycoscientist specializes in complex carbohydrates (e.g. dietary fibre) and gut microbiota, believes that a glycomics-based approach could ensure a minimum loss of the drug before it reaches its destination in the lower GI tract.

The technology involves "caging" existing or new IBD drugs with carbohydrate molecules. Analogous to adding a lock and a cage to a pile of treasures, carbohydrate molecules (lock and cage) are chemically linked to the drug (treasure), protecting it from the premature uptake by the upper GI tract.

"With this approach, we could use much less drug in the treatment," says Sly. "Because the drug is only released at the lower GI tract, it would avoid negative systemic effects."

Unlocking the cage for targeted release

Choosing the right carbohydrate molecules for caging is important, as the cage must be unlocked only at the lower GI tract.

In a previous study published in Nature, Brumer and his team identified a group of gut bacteria commonly found in global populations. These bacteria reside in the lower GI tract and they can chop specific carbohydrate molecules into pieces. This makes the bacteria excellent candidates as "keys" to unlock the glycocage.

In other words, when the caged drug passes through the esophagus, stomach, and small intestine, the drug remains protected inside the glycocage. Upon meeting the group of bacteria in the large intestine, the chemically linked carbohydrate will be chopped off from the drug, thus opening the cage and enabling the drug to assume its job--reducing inflammations at the site.

A network framework catalyzes technology development

The technology, supported by GlycoNet since 2016, has evolved from a proof-of-concept design to in vitro development, and now to in vivo testing.

"What really helps accelerate the technology development is the collaborative efforts from our diverse team of chemists, microbiologists, and clinical scientists across different provinces," says Brumer.

From synthesizing and conjugating carbohydrate molecules to different IBD drugs to validating the effect of caged drugs in biochemical assays, and to testing their real-time therapeutic potential in animal models, the team had preliminary results that indicate the GlycoCage technology could increase the efficacy of IBD drug and reduce inflammation. Yet, there are still more to be tested.

"We are now expanding our tests to different animal inflammation models that mimic diseases like Crohn's and ulcerative colitis. We hope to establish a broad portfolio of glycocaged drugs to treat intestinal inflammation, and validate its potential for translation into human therapies," says Brumer.