A dual-acting small molecule for the treatment of type 1 diabetes

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Project Summary: Over 1.5 million Americans suffer from type 1 diabetes, an autoimmune disorder involving insulin, an essential hormone to blood glucose regulation and overall energy metabolism. When first diagnosed with T1D, it is estimated that the patient’s insulin secreting capacity has been reduced by 70-90%. By this point, the immune system has already targeted and destroyed a vast majority of insulin-producing pancreatic beta cells, in large part, through a barrage of pro-inflammatory cytokines triggering cell death. For a century since its discovery, there have not been any other substantial therapeutic advancements outside of insulin to treat T1D. However, recent therapeutic advancements targeting beta-cell health have resulted in several clinical trials. Asake Biotech, in collaboration with investigators at Ohio University, is developing a small molecule therapeutic that both maintains islet health and enhances insulin secretory capacity to treat two key issues in T1D. In tests of rodent and human pancreatic islets in a dish, our lead compound MSB-3 protected beta-cells from cytokine-induced cell death and stimulated these cells to produce and secrete more insulin without depleting insulin reserves. Preliminary data in non-obese diabetic (NOD) mice, a mouse model of T1D, with established diabetes (blood glucose >400 mg/dL) show that daily MSB-3 treatment stabilizes blood glucose, increases serum c-peptide levels (a marker for insulin production), and decreases pancreatic insulitis (a sign of reduced autoimmunity). This dual action appears to be unique among potential diabetes therapies. However, we have yet to optimize our current lead for potency and safety or to test preclinically for potential next-step trials. Our overarching goal is to use MSB-3 as a starting point for further development of a small molecule with dual activity for the treatment of T1D. Our first specific aim is to thoroughly test MSB-3 for toxicity, protection from cytokine-induced cell death, and estimated pharmacokinetics using liver microsomes. Our second aim is to test MSB-3 in a preclinical mouse model of T1D (non-obese diabetic mice) to determine if our lead compound can prevent or even reverse existing T1D. If successful, these studies will provide insight into potential overlapping pathways between insulin secretion and cell protection. This work will also provide crucial data needed to accrue additional support to further develop this potentially novel and unique treatment of diabetes.