RESEARCH AREAS
Major Research Interests
Worldwide it is estimated that 387 million people have diabetes and this number is expected to increase 53% to 592 million by 2035. In the US, approximately 39 million Americans have diabetes, accounting for 9.3% of the population1. Diabetes is the leading cause of kidney disease and non-traumatic amputations in adults and progressive disease often leads to severe eye, nerve and cardiovascular complications. In 2014 alone, healthcare costs related to treating diabetes and its complications cost approximately 612 billion dollars and are expected to rise.
Despite continuing advances in insulin delivery technology and recombinant insulins, diabetes and its complications still claim the lives of millions of people largely because insulin fails to achieve perfect glycemic control. On the other hand, beta cell replacement therapies including whole vascularized pancreas transplantation and isolated islet transplantation are able to fully restore normoglycemia, achieve insulin-independence and can delay end-organ complications4. Indeed, pancreas transplantation by supplying additional functional beta cells is now highly successful and able to overcome an absolute and relative deficiency of beta cells in patients with Type 1 and Type 2 diabetes, respectively with equal efficacy, thereby providing proof of concept for a broadly applicable beta cell replacement therapy.
However, these therapies suffer from several key limitations: the shortage of organs, inconsistent quality of donor organs, and the need for life-long immunosuppression to prevent allograft rejection and autoimmune recurrence. Thus, an ideal goal would be to provide insulin-producing tissue from an unlimited and replenishable supply of human pluripotent stem cells (hPSCs) and to engineer these cells to provide prolonged survival, or escape from immune recognition and destruction entirely, using currently available genome editing technologies. Moreover, as therapeutic hPSC derivatives have the potential for forming teratomas or undergoing malignant transformation, provision of an inducible suicide gene would offer protection from this occurrence.
Using these strategies, it may be possible to achieve an unlimited supply of consistently high quality “universal human beta cells” and overcome allo-and autoimmune mechanisms of destruction and protect from the development of rogue malignant cells in non-immunosuppressed patients, thereby providing a beta cell replacement therapy for millions of patients with insulin-dependent diabetes, including both Type 1 and Type 2 diabetes.
In addition to stem cell research, our research enterprise conducts pancreas and kidney transplant outcomes research using our UW Transplant Database.
Current Projects
The lab, under the co-leadership with Dr. Sackett, principal scientist and co-investigator, employs animal models and cutting-edge technology to understand the development of the beta cell fate from human pluripotent stem cells, improve transplantation outcomes, build a better home for stem cell derived islets and cadaver islets, and use genetic tools and animal models to understand and improve the immunogenicity of stem cell-derived beta cells. The following funding is in support of these ongoing projects.
• Institute for Clinical and Translational Research (ICTR): Interrogating the Human Islet Extracellular Matrix Niche
Using mass spectrometry imaging we will comprehensively characterize the ECM composition of native human islets free of the artifacts of enzyme-mediated ECM damage and compare the matrisome to that of SCILCs.
• JDRF An Inducible Genome Engineering Approach for Preventing Immune Rejection of hESC-derived Beta Cells
The goals of this project are to generate and validate various hESC lines that harbor modifications in relevant immunomodulatory genetic loci and test these in a diabetic mouse model and assess immune responses.
• State Economic Engagement and Development Award (SEED) – D2P. Reversal of Diabetes in Mice by Human Pluripotent Stem Cell Beta Cells
This study will evaluate the effective dose and transplant site in a novel immunodeficient mouse model of diabetes using hiPSC-beta cells in collaboration with RMS, Inc.
• Department of Defense: Engineering and Invisibility Cloak for Stem Cell Beta Cells for Treating Diabetes
The overall strategy is to use advanced genome editing strategies to engineer hESC-derived pancreatic islet like-clusters to possess complete immunoprotection, or an “invisibility cloak” form human allogeneic immune responses, without the need for encapsulation or immunosuppression.