Research Project
10150610
Targeted Therapy for Type 1 diabetes Abstract Type 1 diabetes (T1D) is an autoimmune disease characterized by specific destruction of pancreatic insulin- producing beta cells, mediated by beta-cell-directed autoimmunity involving autoreactive T cells and islet autoantibodies. While blood glucose levels can be controlled with diet and medication, a cure for the disease remains elusive, and T1D cannot be prevented or reversed in humans. While T1D is easy to prevent in the nonobese diabetic (NOD) spontaneous mouse model, reversing T1D in mice is more difficult. Autoreactive T cells, in particular the effector memory CD8 subset, cause T1D by destroying insulin-producing islet beta cells. We have recently shown that soluble CD137 (sCD137) is secreted by regulatory T cells in both mice and humans, induces T cell anergy, and effectively treats acute T1D. Treatment of acute-onset T1D in NOD mice with murine sCD137 prevents progression of disease and demonstrates proof-of-concept for a novel therapeutic approach to reverse T1D. During this Phase 1 project, we will engineer a CD137-Fc construct with prolonged half-life and improved T cell targeting. The activities of sCD137, an untargeted sCD137-Fc and the targeted version will be compared in vitro and in a humanized NSG mouse model. These studies will provide the basis for translation of this discovery from the murine models to humans to create the first disease-modifying treatment for T1D.
