Targeting T1D with Novel Inflammasome Inhibitors

Type 1 diabetes (T1D) is an autoimmune disorder that mainly affects young children. The major inciting event is massive autoimmune destruction of pancreatic islet beta-cells by infiltrating immune cells (insulitis). However, despite enormous amounts of research, the underlying mechanism of T1D progression is not well understood. We believe that inflammation plays an important role in T1D progression and development by causing beta cells dysfunction and apoptosis. No approved drugs targeting the destruction of beta-cells requiring patients to take insulin the rest of their lives. There is a profound need for disease-modifying therapies for the treatment of T1D. We hypothesize that targeting the innate immune through NLRP3 inflammasome inhibition to block cytokines IL-1β and IL-18 may have promise for the treatment of T1D. In this proposal we designed and developed very potent and selective inflammasome inhibitors which target the inflammasome and we characterized their protein targets and mechanism of action. Our preliminary results show that these compounds are able to preserve blood glucose levels in accelerated T1D mouse model.