Developing a Cell Replacement Therapy to Evade the Immune System and Eliminate Type 1 Diabetes
Fifteen New England scientists, including the Diabetes Center of Excellence (DCOE) at UMass Chan Medical School, are collaborating to develop a cell replacement therapy that will evade the immune system and provide insulin independence for people living with type 1 diabetes (T1D). The multi-institutional research team is funded by Breakthrough T1D (formerly JDRF), which appointed UMass Chan DCOE Co-Director David Harlan, MD, to lead the group in 2022.
Dr. Harlan heads up a clinical study with diabetes patients from UMass Memorial Health who voluntarily donate blood, from which functioning stem cell-derived insulin-producing islets are created.
More than two decades ago, Douglas Melton, PhD, had the idea of using embryonic stem cells to develop functional pancreatic islets. His lab at the Harvard Stem Cell Institute successfully created beta-like cells, similar to those destroyed by the immune system of people with type 1 diabetes.
“For the past 40 years, I've helped patients manage diabetes while focusing my research on the cure,” said Dr. Harlan, the William and Doris Krupp Professor of Medicine and Co-Director of the UMass Chan Diabetes Center of Excellence. “In 2006, while Chief of Intramural Diabetes Research for the NIDDK/NIH, I heard Dr. Melton describe his stem cell plans to recreate type 1 diabetes in the humanized mice being developed between UMass Chan Medical School and The Jackson Laboratory. It inspired my move to UMass Chan in 2009 to join Dr. Dale Greiner in co-directing our research efforts.”
In 2021, Vertex Pharmaceuticals released initial clinical trial data about the first person to receive transplanted stem cell-derived pancreatic islets. The results proved the manufactured cells work. However, they still require immunosuppressive therapy and its many associated health risks.
Sam Redick, PhD, leads a team of five in the Pappas Stem Cell Differentiation Core at the UMass Chan DCOE, responsible for growing stem cell-derived islets for various collaborative research projects.
Scientists at the UMass Chan Medical School Diabetes Center of Excellence, Joslin Diabetes Center, University of Toronto, and The Jackson Laboratory are investigating ways to genetically engineer those beta cells to protect them from autoimmune attack in people with T1D. Genetically modified targets are being tested in our novel models of human type 1 diabetes.
"The holy grail of this research collaboration will be a cell replacement therapy that eliminates the need for immunosuppressant drugs," said Dr. Harlan
Dale Greiner, PhD and Michael Brehm, PhD, are transplanting genetically modified stem cell-derived beta cells into our novel “humanized” mouse models of type 1 diabetes to determine if they’re invisible to the immune system as intended.
The Brehm and Greiner labs study the relationship between the donors’ insulin-producing cells and their immune cells in various situations and stages of the disease process. Experiments are conducted continuously to observe how the cells interact and to determine where and how rejection occurs.
“When Lenny [Dr. Shultz at The Jackson Laboratory] and I were developing the first ‘humanized’ mice in the 1980s, we only dreamed that one day they’d be optimized to where we have them now,” said Dr. Greiner, The Herman G. Berkman Chair in Diabetes Care Innovation, Professor of Molecular Medicine, and Co-Director of the UMass Chan Diabetes Center of Excellence. “Transplanting stem cell-derived pancreatic cells that have been genetically modified to become ‘invisible’ to the immune system, into our humanized models, allows us to observe T1D like never before.”
This cutting-edge research is more than just a job for Dr. Brehm, The Harvey A. Shultz Chair in Diabetes, Associate Director of the UMass Chan Diabetes Center of Excellence, and Co-Director of the Humanized Mouse Core Facility at UMass Chan Medical School.
“As someone who lives with type 1 diabetes, I’m invested both personally and professionally in finding a cure,” he said. “This is an incredible group of scientists from top New England institutions collaborating to bring us one step closer to a potential cure.”
René Maehr, PhD, is using advanced genetic editing tools to investigate better ways to protect transplanted islets. He is also working on strategies to educate immune cells to eliminate the autoimmune attack post-transplantation.
Sally Kent, PhD, examines the cells before transplantation into the humanized mice and again after being removed following the various experiments to analyze how the immune system recognizes (or ideally doesn't) the modified stem cell-derived islets. Dr. Kent is collaborating with Jason Gaglia, MD, at Joslin Diabetes Center, to determine how cell function and characteristics changed post-transplantation. The process must be measured and proven to be safe before proceeding towards clinical trials. Dr. Gaglia began his career as a clinical research fellow on the islet transplant team in Dr. Harlan’s lab at the National Institutes of Health in 2000.
Jennifer Wang, MD, a physician-scientist in the field of T1D and viral immunology at UMass Chan and UMass Memorial Health, is an expert in infectious disease. Her lab is exposing stem cell-derived beta cells to viruses, infections and inflammation that they may face, to study how they react.
Accalia Fu, PhD, has developed a co-culture system to test if glucose arginase 2 (Arg2) and glutathione (GSH) pathways protect stem cell-derived islets from immune attack. Her lab is investigating how these pathways shape the metabolic milieu of pancreatic islets and local immune cell activities. Her system utilizes technologies including metabolomics, proteomics, and transcriptomics.
Jessica Spinelli, PhD, identified a molecule in mitochondria that helps to reroute energy production when oxygen levels drop. This discovery could provide new therapies for oxygen-starved conditions, including cell replacement therapies. The Spinelli lab is investigating how this could protect islets after transplantation.
The team meets regularly to update each other about experiments and progress. They enjoy collaborative science and are less concerned with individual credit, but instead are focused on the ultimate goal.
The seed funder of this collaboration initiative is UMass Chan DCOE Visiting Advocacy Committee member John Cammett. “My desire to find a cure is inspired by my mom living with T1D for almost 60 years. We have supported several of these researchers individually before. But the Center of Excellence in New England gives me tremendous optimism because it brings together the brightest minds, with a laser-sharp focus on developing cures."
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