Author: Cumming School of Medicine Staff
Grant Silbernagel, who lives with Crohn's disease, feels hopeful about new UCalgary research to reverse damage and better inform Crohn's treatment. Photo Courtesy: Grant Silbernagel
For more than a decade, Calgarian Grant Silbernagel, 61, has lived with Crohn's disease (CD), the same inflammatory bowel disease his father struggled with and his adult son also shares.
"When you're in a flare, it's debilitating you're totally tied to facilities. Constant trips to the bathroom, diarrhea, pain and often bleeding. I love golfing, but there was no way I could go golfing because I couldn't stay on the course long enough," Silbernagel says.
The self-employed interior renovator and good-natured father refers to life with CD as his "adventure." He has see-sawed in and out of remission many times trying several medications, including one that made his bones so weak he suffered spinal compression fractures requiring surgery. Treatment for another serious illness damaged his colon so severely that he needed a surgery to remove 40 centimetres of his intestine.
As we mark Crohn's and Colitis Awareness Month this November, Silbernagel hopes two newly-funded research projects at the Cumming School of Medicine's Snyder Institute for Chronic Diseases will change his life and those of approximately 270,000 Canadians living with inflammatory bowel disease. The University of Calgary was recently awarded philanthropic gifts from The Leona M. and Harry B. Helmsley Charitable Trust, totalling nearly US$2.1 million (C$2.6 million) to support this research.
Molecular mystery
Dr. Cathy Lu, MD, is on the hunt for clues to identify which Crohn's disease (CD) patients will develop scar tissue in their intestines, which causes narrowing and leads to blockages. These blockages can make CD patients so sick they need to be admitted to hospital or need surgery. Current drugs approved to treat their intestinal damage seem to have limited effect.
In the first study of its kind, Lu, along with Dr. Simon Hirota, PhD, and Dr. Antoine DuFour, PhD, are working to pinpoint the protein signatures measurable signs within some of the molecules found in our bloodstream that tell the intestinal walls of CD patients to grow scar tissue, causing them to narrow.
It's a first step to developing new precision medical treatments and preventive strategies for CD patients. Precision medicine represents a new and disruptive approach to the way health care is delivered, using information from a person's genes, biomarkers, proteins and other factors to prevent, diagnose and treat disease.
"For example, using a simple blood test rather than a colonoscopy or MRI scan, which are not always quickly available, will help us detect if a narrowing is present before end-stage changes occur, and will inform us when to recommend surgery or changes in medications leading to better outcomes and quality of life for patients," says Lu.
From left: Simon Hirota, Cathy Liu, Antoine Dufour and Derek McKay. Photo by Bruce Perrault, University of Calgary
About half of all patients with CD experience narrowing of the intestines, whereas other patients with CD never seem to develop this complication. In a small pilot study, Lu's team previously confirmed that the protein signatures for each of these types of CD are different.
Now, thanks to a nearly US$1.3 million gift that's C$1.6 million from the Helmsley Charitable Trust to the University of Calgary, the team will forge ahead with their new two-year investigation to gather, image and compare the protein signatures of CD patients with and without narrowed intestines, along with those of healthy patients. Participants will be recruited through UCalgary's inflammatory bowel disease (IBD) clinics for the project, titled Quantitative Proteomic Profiling of Fibrostenotic Crohn's Disease Patients.
Crohn's disease-fighting immune cells
A second UCalgary study, made possible with more than US$770,000 C$950,000 funding from the Helmsley Charitable Trust, aims to enhance treatment and prolong remission for people living with CD. The investigation by Snyder Institute director Dr. Derek McKay, PhD, and co-applicant Dr. Remo Panaccione, MD, will lay the groundwork for future testing of a personalized cellular immunotherapy to treat CD.
The approach proposes to use the body's own immune system cells to treat illness. McKay and his team previously discovered that interleukin-4 activated macrophages (M(IL-4)) a pro-healing type of white blood cell in the immune system can reverse colitis in lab tests. The group believes future custom cell therapies created from an inflammatory bowel disease patient's own M(IL-4) could effectively reduce their inflammation, improve healing and extend disease remission as an add-on to drugs currently approved for IBD.
"To do this, we would take macrophages from a patient in remission, treat the macrophages in very controlled conditions with an immune signal the interleukin-4 that switches it into repair mode, then we put that macrophage back into the same patient. The macrophage finds the diseased intestine and helps repair it," McKay says.
He adds that the grant from the Helmsley Charitable Trust is a real opportunity to advance knowledge of macrophage biology in patients with Crohn's disease a major form of IBD. If successful, it would position UCalgary to produce a good manufacturing product (GMP) macrophage that aligns with Health Canada's standards for treatment in patients, with the goal to launch a clinical trial. The patient would receive their own macrophages back as a treatment to promote wound healing.
This is not a drug manipulation, this is not taking cells from a sibling, it's using a patient's own cells and encouraging them to take on a task they have naturally evolved to do, and then putting those cells back into the patient to reduce inflammation in the colon.
Derek McKay
While this kind of immunotherapy has been used in a limited way to treat other diseases, it's a bold and new approach for CD. McKay and Panaccione will be recruiting patients with CD, both active and in remission, for the three-year study project beginning in April 2022. The study, titled Interleukin-4 Activated Macrophages (M(IL4)) for Personalized Cellular Immunotherapy to Treat IBD, will also help identify which patients will not respond to M(IL-4) immunotherapy, why it won't work for them, and the markers in their macrophages that flag this.
"We are committed to supporting efforts that can lead to marked improvements in the lives of people with Crohn's disease while we pursue a cure," says Dr. Laurie Churchill, a program officer at Helmsley. "The University of Calgary is a leader in Crohn's disease research and these projects hold promise for making strides towards both of these goals."
The Helmsley Charitable Trust has supported medical research related to Type 1 diabetes and Crohn's disease, along with place-based programs, since it began active grantmaking in 2008. In addition to the Snyder Institute's world-class IBD research, Helmsley supports Crohn's disease research at more than 70 institutions worldwide. Their funding in this field over the past decade is approximately $500 million, including more than $3 million in funding to UCalgary this year for medical research projects to tackle CD.
For the past year, a monthly injection of biologic drugs has kept Silbernagel's flare-ups at bay. He's taking more time to enjoy fishing, camping and other outdoor hobbies, because he knows too well how precious good health can be.
"Going through my life and also seeing the problems my own child had, I would love nothing more than to see this research lead to new diagnostics and treatment for patients," says Silbernagel. "My son was diagnosed with Crohn's at 12 and by age 26 he didn't have a colon. To prevent that for others and especially for young people that would be a miracle."
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Cathy Lu is a gastroenterologist and clinical assistant professor in the Cumming School of Medicine's (CSM) Department of Medicine. She is interested in bowel ultrasound in IBD, with a special interest in Crohn's disease strictures (narrowing).
Derek McKay is the director of the CSM's Snyder Institute for Chronic Diseases, and a professor with the Department of Physiology and Pharmacology at the University of Calgary. He was recently awarded the Crohn's and Colitis Canada Finkelstein Award, which recognizes an individual whose contributions reflect excellence, either through a particular accomplishment or through continuous efforts over time.
Remo Panaccione is the current assistant dean of MD admissions at the University of Calgary, a professor with the Department of Medicine, serves as director of IBD Research and is the Crohn's Colitis IBD Chair.
Antoine Dufour is an assistant professor with the departments of Physiology and Pharmacology and Biochemistry & Molecular Biology as well as a member of the McCaig Institute for Bone and Joint Health at the University of Calgary.
Simon Hirota is an associate professor with the Department of Physiology and Pharmacology at the Snyder Institute for Chronic Diseases at the University of Calgary and the Canada Research Chair (Tier 2) in Host-Microbe Interactions and Chronic Disease.
The Snyder Institute for Chronic Diseases was named in 2008 in honour of Joan Snyder and her parents, Calvin and Phoebe, whom Ms. Snyder credits for teaching her the value of philanthropy. It is a group of more than 125 clinicians, clinician-scientists and basic scientists who are impacting and changing the lives of people suffering from chronic, infectious and inflammatory diseases, including sepsis, MRSA, cystic fibrosis, Type 1 diabetes, inflammatory bowel disease, and chronic obstructive pulmonary disease.
The University of Calgary is uniquely positioned to find solutions to key global challenges. Through the research strategy for Infections, Inflammation, and Chronic Diseases in the Changing Environment (IICD), top scientists lead multidisciplinary teams to understand and prevent the complex factors that threaten our health and economies.
