Engineering an Invisibility Cloak for Stem Cell Beta Cells for Treating Diabetes
Abstract
Diabetes is a critical health problem, and despite continuing advances in insulin delivery technology, diabetes and its complications still claim the lives of millions of people. Patients frequently develop progressive kidney, eye, nerve, and heart disease due to failure to adequately control blood sugar levels. Based on the ultimate goal of achieving better blood sugar control, pancreas and islet transplantation procedures were developed and refined. Unfortunately, these therapies depend on the availability of cadaver organ donors of which there are too few to supply enough tissue for all of the patients with type 1 diabetes, type 2 diabetes, and other forms of diabetes. Not only are there too few pancreases, islets, and beta cells available, but the quality of the supplies is often suboptimal. Furthermore, the cadaver source of the transplanted cells mandates heavy doses of potentially toxic and diabetes-causing immunosuppressive medications. The dual risks of rejection and deleterious effects of immunosuppressive medications often result in severe morbidities and early mortality in transplant recipients. Human pluripotent stem cells (hPSCs) represent an exciting potential solution to this clinical problem, as these cells have the ability to replicate to generate a nearly limitless supply and have the intrinsic biological ability to differentiate into insulin-secreting beta cells in culture, which can reverse diabetes in mice. After years of research, we and others have demonstrated that hPSCs can be directed to form enriched populations of beta-like cells in culture, exhibiting physiological insulin secretion characteristics similar to those of normal human islets, and capable of curing diabetes in mice. This major achievement of generating glucose-responsive and physiologically mature hPSC-derived beta cells brings an unlimited therapy one step closer to clinical reality. Using state-of-the-art genome editing strategies, we have generated hPSC cell lines with up to four modifications in key immune response genes. These cells could provide a potentially renewable supply of consistently high-quality “universal off-the-shelf” beta cells for transplantation. Here, we propose to evaluate the insulin secretory function of these novel cells both in culture as well as their ability to cure diabetes in mice. Subsequently, using two different model systems, we will determine whether they are vulnerable to human immunological attack and destruction in mice that have a human immune system. We anticipate the modified cells will be relatively protected from rejection in these humanized mouse models, but if they are not completely protected, we propose to perform an unbiased genomic screen for additional genes and molecules that can further boost the survival and prevent rejection of the stem cell beta cells. Once candidate immunomodulatory genes (genes that modify immune responses in culture tests and in human immune system mice) are identified, advanced multiplexable genome editing techniques provide a powerful platform for making additional modifications to our existing lines in the future. We believe successful completion of this project will demonstrate enabling strategies to engineer a “universal, off-the-shelf, immunologically protected” human stem cell-based beta cell replacement therapy for all.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010670
Entities
People
- Danwei Huangfu
Organizations
- Sloan-Kettering Institute
- United States Army