Discovering Novel Treatments

Dr. Harry Brumer  | University of British Columbia
Research: A glyco-caged peptide delivery system to advance IBD treatment
Date: 2019-2021
Amount: $50,000

Peptides may offer a new therapeutic approach for IBD. Thus far, these peptides are delivered through IV or directly into the colon, limiting their broad use in clinic. New approaches to deliver them to the lower gastrointestinal tract are needed to realize the full potential of these drug candidates.

Dr. Brumer and his team are working on a new technology where the peptide will be packaged as an inactive pill that can be taken orally and only becomes active in the lower gut. These “glyco-caged” peptides become active by gut bacteria-specific enzymes that release the peptide from the glyco-cage. They will test this idea by synthesizing this glyco-caged peptide, evaluating the release of the active peptide from the glyco-cage by human gut bacterial enzyme in vitro, then testing the glyco-caged drug using a mouse model of IBD.

Dr. Jean Sévigny | Université Laval
Research: Investigating NTPDase8 as a new biological therapy for IBD
Date: 2019-2020
Amount: $50,000

Identifying the pathways responsible for the body’s inflammatory response in the gut is essential to understanding how IBD develops and discovering new therapeutic targets and strategies. This research lab studies extracellular nucleotides, which are released by cells that amplify inflammation, and which may be an important mechanism for doing so in the bowel.

They have found that blocking these nucleotides from signalling at the intestinal surface prevented colitis in a mouse model. In addition, they found that an enzyme in that same area, NTPDase8, can destroy the nucleotides and prevent intestinal inflammation.

In this new project, the team seeks to develop a soluble form of NTPDase8 that could be administered to prevent the activation of nucleotide receptors in the bowel – and, in doing so, protect the intestine from inflammation. They will seek to investigate the enzyme’s therapeutic potential in IBD.

Dr. Laura Sly | University of British Columbia
Research: Targeting intestinal inflammation caused by SHIP deficiency
Date: 2019-2022
Amount: $375,000

Biologics are a newer drug class that has proven successful at reducing inflammation along the gut and reducing the difficult symptoms and subsequent burden of IBD for many people. However, up to 20% of people with IBD do not respond to biologics – and up to 40% may eventually stop responding. New treatment options are essential, as is a greater understanding of what drives such inflammation.

This research team found that loss of a protein called “SHIP” causes gut inflammation in mice that mimics Crohn’s disease. They also found SHIP protein levels drop to below 10% of what is considered normal in a sub-group of people with Crohn’s. Colleagues at SUNY Upstate Medical University found that people with Crohn’s who show low SHIP levels have a history of severe disease that does not respond well to therapy.

SHIP normally blocks inflammation in cell and animal models. This project will treat cells that are missing SHIP with a new inhibitor that blocks the specific inflammatory pathway activated in these cells. The team will do so in cell models, in mice that are missing SHIP, and in blood cells from people with Crohn’s who have low SHIP activity.

Together, these studies will test the ability of their new treatment to treat Crohn’s inflammation where SHIP levels are low – a group of people who currently have no effective treatments.

Dr. Carolina Tropini | University of British Columbia
Research: Microbial control of gut environment in IBD
Date: 2019-2022
Amount: $375,000

Gut health is closely related to our microbiota, a unique consortium of trillions of microbes that produce compounds that are absorbed into our blood, providing nourishment and affecting our health. The gut’s physical properties, such as salt concentration, acidity, and temperature are tightly regulated by human-microbe interactions.

However, in IBD, this environment and the microbiota’s function are dramatically altered. This is a critical element in IBD, yet we know little about how this altered environment impacts the gut microbiota and disease progression. Here, researchers will use new experimental and computational methods to study the connection between the gut microbiota, gut microenvironment, and immunity in experimental models of IBD and in human IBD tissues. They will identify characteristics of the gut environment and microbiota that can help predict disease state.

This research will analyze isolated bacteria and study how they respond to and modify their environment with the eventual goal of restoring a healthy gut. The team seeks to develop algorithms to predict disease state and drug effectiveness, as well as microbiota-based therapies for IBD.

Dr. Bruce Vallance | Children's and Women's Health Centre of British Columbia
Research: Discovering how dangerous bacteria damage the gut and developing therapeutics to clear them
Date: 2019-2022
Amount: $375,000

Both Crohn’s disease and ulcerative colitis (UC) are thought to develop because of changes in gut bacteria that activate the immune system, causing it to attack these bacteria, as well as intestinal tissues and thus cause chronic inflammation. After identifying a dangerous bacteria in the intestines of many people with UC, researchers found these bad bacteria stick to the intestinal wall, where they release a poison which damage the gut.

This project will advance this work in several ways, using cell and animal models. Researchers will seek answers as to how the bacterial poison damages gut cells and triggers inflammation. They will test the effectiveness of a new drug that can prevent these bacteria from sticking to the intestine, and explore what factors in the intestine make some people susceptible to this infection.

Taken together, the project will help define the role played by bad bacteria in driving gut inflammation, and lead to new therapeutic targets to clear the bacteria in different patients. It will also identify what features of the gut increase the risk of someone carrying these bacteria.

Dr. Stephen Vanner | Queen's University
Research: Testing new IBD abdominal pain relief drugs that limit or prevent side effects
Date: 2019-2022
Amount: $375,000

One of the greatest unmet needs for patients with IBD is abdominal pain. Opioid-based pain relievers are the most effective drugs available but carry troubling side effects that limit their use.

This study will examine novel drugs that are effective painkillers yet with minimal side effects—made possible through advances in drug development and increased knowledge of how drugs bind to pain-sensing neurons found in the gut. There, inside these neurons, exist receptors called “G-protein-coupled receptors” (GPCRs) that are linked to pathways that stop pain signals from reaching the brain.

Researchers will chart course with two opioid-based strategies that have breakthrough potential. The first strategy involves using opioid drugs that target endosomes (organelles located within the cell) and block pain signals in a sustained fashion. The team will use specific drugs that bind to typical opioid receptors on the neurons, but only selectively stimulate the intracellular pathways leading to these endosomes. They will also use novel opioid nanoparticles that deliver the drug straight to the endosomes, especially during episodes of inflammation.

Their second strategy calls for a pH-sensitive opioid drug designed only to react with opioid receptors in neurons of inflamed tissues, such as the intestine where tissue is acidic and has lower pH levels. In principle, these drugs should not affect non-inflamed tissues, thus minimizing adverse side effects.

Dr. Elena Verdu | McMaster University
Research: Investigating proteolytic imbalance in bacteria for new colitis therapeutic targets
Date: 2019-2022
Amount: $375,000

This research team found that certain bacteria in the stool of patients with ulcerative colitis (UC) have high proteolytic activity. Their presence in the stool of some individuals at risk for IBD is associated with onset of disease.

They will investigate this closely by using stools from patients with active UC, those at risk for IBD who were followed for years until they developed UC, as well as those at risk who did not develop UC. From the latter, they seek to identify bacteria that may naturally inhibit the proteolytic activity of UC-causing bacteria. (This will take place in mouse models with bacteria isolated from the guts of patients with UC as well as healthy controls.)

While there is growing interest in how to influence the gut microbiome in IBD, we lack bacterial targets as well as mechanistic information. This project targets specific enzymes that cause inflammation and colitis, which will help design more effective and specific microbiome-based therapies for UC – such as probiotics designed to stop proteolytic activity, or strategies to make fecal transplantation more efficient.

Results will help identify new bacterial markers and new therapeutic targets to inform prevention and early detection of UC.

Dr. Robert Young | Simon Fraser University
Research: New EP4 agonist ‘prodrugs’ to reduce symptoms and safely repair and protect the intestinal lining
Date: 2019-2022
Amount: $375,000

In ulcerative colitis (UC) and Crohn’s disease, the intestinal lining is broken down by inflammation and bacteria can enter and impair health, raising over time the risk of developing perforations – a life-threatening crisis. Many drugs treat inflammation but not its cause, and can in fact prevent the body’s ability to repair the intestinal lining. We need a drug that instead will stimulate that repair, and protect the gut lining in UC and Crohn’s.

Prostaglandins are hormones that interact in the gut with receptor molecules – most importantly, EP4 – to protect the lining. EP4 agonists are promising drugs with early evidence of success in animals and humans, but they can also cause side effects such as low blood pressure, headaches, and diarrhea.

This research team has designed novel EP4 agonist “prodrugs”, inactive molecules that deliver and release the active drug to specific locations. In this study, they will design such prodrugs to stay in the intestines after swallowed and not enter the bloodstream. Gut enzymes will convert the prodrugs to active EP4 agonists right where needed and stimulate the intestine to repair itself. If any active drug is absorbed, it is designed to be quickly removed by the liver. Researchers will initially test and monitor the prodrugs’ effectiveness in mice.

Such treatments are highly sought after and have great potential in relieving IBD symptoms and protecting patients.