Greg Korbutt (left) and Andrew Pepper are members of a research team aiming to develop insulin-producing stem cells that won’t trigger an immune response, so transplant patients wouldn’t need to take anti-rejection drugs. (Photo: Faculty of Medicine & Dentistry, May 2019)
University of Alberta researchers are among two Canadian research teams chosen for significant new funding from the government of Canada and JDRF Canada to develop new stem cell-based therapies for treating Type 1 diabetes.
The projects will each receive $1.5 million from the Canadian Institutes of Health Research Institute of Nutrition, Metabolism and Diabetes (CIHR-INMD), along with matching dollars from JDRF Canada, for total funding of $3 million per project over five years. The funding investment marks the anniversary of the Canadian discovery of insulin 100 years ago, a significant turning point in the work to defeat diabetes.
While notable progress has been made over the last century, new therapies and a cure for diabetes remain elusive. The funding is hoped to help accelerate the development of new treatments.
Building a better cell for transplantation
Greg Korbutt and Andrew Pepper with the U of A’s Department of Surgery are co-principal investigators on a project led by Cristina Maria Nostro out of the University of Toronto. Since islet-cell transplantation was established through the Edmonton Protocol in 2000 as a therapy for patients with Type 1 diabetes, hundreds of patients around the world have benefited from the treatment. However, donor scarcity, poor islet survival after transplant and the need for patients to take immune-suppressing drugs have limited who can be offered the therapy. The team’s project hopes to find ways to expand islet transplantation by developing insulin-producing stem cells that won’t trigger an immune response.
“They would be hypoimmunogenic, which is a fancy way of saying ghost-like cells,” said Pepper, an associate professor of surgery and member of the Alberta Diabetes Institute (ADI). “The immune system won’t see them, in theory. So if we transplant these cells, hopefully we won’t need anti-rejection drugs.”
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The team also hopes to develop and test a method of transplantation for the stem cells that would be safer for the patient and more easily monitored. Traditionally, patients receiving islet transplantation through the Edmonton Protocol would have islet cells delivered directly to their liver. In their project, the team will instead deliver stem cells to a site directly underneath the skin.
“We don’t like to rely on one chance or one therapy. So let’s say these hypoimmunogenic dose cells are not really as ghost-like as we think; we want to be able to deliver immunosuppressive drugs just to the graft itself, just to the transplant site,” said Pepper.
“We hope that combination approach to the hypoimmunogenic cells and our localized drug delivery will really decrease any risks or toxicity, and hopefully improve the transplant function of these stem cell-derived islets.”
If successful in its first two goals, the team will move to a third stage of the project, driving the therapy closer to the clinic by developing the cell line at a clinical formulation that would be acceptable for human transplantation. It would also lead to a clinical trial.
The process would rely on Korbutt’s expertise as director of the U of A’s Alberta Cell Therapy Manufacturing facility – and would be a step up from current islet transplantations that rely on donor islets.
“When we look clinically at our patients that are getting human islets from organ donors, everybody’s getting a different cell prep and with completely different viability function. So it’s really hard to look at it and go, ‘Well, how do you change things when everybody’s getting different cells?’” said Korbutt. “If we can develop a universal stem-cell line, all would be getting the same cells. Then you can compare transplantation efficacy in all these patients.”
“So if we could have a universal cell that doesn’t require immunosuppression, we can really expand the amount of patients around the world who could get transplants because we’re not limited by supply. Right now it’s a very small percentage that are eligible,” noted Pepper.
“This isn’t just theory. There’s actually a practical path to the clinic using Good Manufacturing Practice-grade cells should the data warrant that direction,” he added.
Developing a mature insulin-producing stem cell
Patrick MacDonald, professor of pharmacology and ADI member, is a co-principal investigator on a study led out of the University of British Columbia to develop a more mature insulin-producing stem cell for use in transplantation.
“Although we can make insulin-producing cells from stem cells, the cells that are produced currently are what you might call immature,” said MacDonald. “We can push the cells all the way up to something that resembles insulin-producing cells in infants. We want to improve the functionality of these cells so they can secrete as much insulin as the mature ones.”
According to MacDonald, when immature cells are transplanted into animals, they naturally mature on their own. Though it’s tempting to assume the same thing may happen in humans, it’s still unknown whether that’s actually the case. Transplanting immature stem cells into humans would also introduce ways the cell development could go awry, potentially causing long-term harm.
Getting a better understanding of how the stem cells mature will provide valuable hints that could pave the way for future therapies for patients with Type 1 diabetes, said MacDonald. He also believes the knowledge will prove valuable for researchers working on therapies for Type 2 diabetes.
“Genetic signals that control the development and maturation of islet cells might be important for the genetic risk of Type 2 diabetes. The knowledge that we generate from these kinds of studies can be more widely applicable than I think people often appreciate.”
MacDonald’s role on the team will be helping determine what signals are needed to advance stem cells further along the maturation pathway. His team’s focus has been on studying human islet cells taken from organ donors and mapping, or making an atlas, of gene expression and function in the cells. In this project, they will contrast the progression of stem cell-derived insulin-producing cells with primary islet (beta) cells.
“This could give us some clues into how we might push things forward,” said MacDonald.
MacDonald said he has seen remarkable progress in diabetes research since he first entered the field more than two decades ago, but acknowledged much more work is needed. And though it’s unclear when the next big breakthrough will happen, he is confident that important steps are being taken.
“I want people to know that there are a lot of very committed and invested scientists across the country and across the world, working to better understand Type 1 diabetes, with an aim to push forward better treatments, and someday, to cure the disease,” said MacDonald.
“There are many different aspects that need to be addressed. The work’s not done. We’ve got a lot ahead of us, but we will continue to push forward.”
| By Ross Neitz
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