People with Down syndrome have an increased risk of certain cancers, congenital heart defects, autoimmune diseases, and cognitive disorders like Alzheimer’s disease. What do all of these conditions have in common? They all involve irregularities in how the immune system is functioning. While immunotherapies – types of treatments that harness the immune system to fight disease – can be helpful in treating these conditions, they may not work the same in patients with Down syndrome because these patients already have overactive immune systems. So how do we develop and test immune therapies that can be used to fight disease in patients with Down syndrome? This is where the creative research of Division of Transplantation Assistant Professor Matthew E. Brown, PhD comes into play.
With a new four-year, $2.9 million Resource-Related Research Project (R24) grant from the National Institute of Allergy and Infectious Diseases, Brown’s lab will be developing new regenerative medicine (i.e., “hypoimmune”) cell therapies for people with Down syndrome by studying the unique biology of the immune system in Down syndrome and doing so in the context of transplantation.
“With hypoimmune cell therapies, we genetically modify a type of stem cell that we can make into almost any type of cell in the body; these cells are called induced pluripotent stem cells, or iPSCs,” Brown explained. “These iPSCs are designed to evade the immune system, which may allow us to transplant them into recipient patients without the patient needing to take powerful drugs to suppress their immune system, which can have side effects.”
Brown’s lab studies the use of iPSCs in “humanized” mouse models, in which mice have been genetically modified and implanted with human tissue to create a human immune system within the mouse. This allows researchers to study the potential response of the human immune system to transplant treatments. For this study, Brown’s team will be using a new humanized mouse model that is specific to Down syndrome, the Thymocyte-Hu mouse, which was developed by their lab. They will also develop a new version of another, advanced type of humanized mouse, the NeoThy mouse, which will model the biology of the immune system that is present in Down syndrome. Finally, they will distribute the biological material and data resources to use these mice and the hypoimmune cells to the Down syndrome research community so they can be used in future studies. Brown’s team will also provide access to the mice through the UW Humanized Mouse Core, which Brown directs.
“Collectively, the results of this study and the resources that we plan to make available for future research could help overcome the limitations of current pharmaceutical treatments and cell therapies for a number of diseases that impact people with Down syndrome, fostering high-impact discoveries and potential new therapies for people with Down syndrome,” said Brown. “We’re incredibly grateful to the National Institutes of Health for supporting this research, which has the long-term potential to save lives and improve health-related quality of life for people with Down syndrome.”