Development of a Novel Oral Enzyme Therapy to Prevent and Treat T1D

The pathogenesis of Type 1 Diabetes (T1D) is now understood to involve the destruction of pancreatic Beta cells through an immune/inflammatory response that likely has its origins from the intestinal microflora. Previous studies have shown that endotoxin injection substantially worsens streptozotocin (STZ)-induced T1D, whereas TLR-4 KO mice are partially protected from developing T1D. Recent studies have demonstrated that translocation of gut bacteria to pancreatic lymph nodes trigger NOD2 inflammasome activity, contributing to STZ-mediated T1D. This new understanding about the pathogenesis of T1D has been reviewed by Josef Neu and he suggests that an aberrant intestinal microbiome, a leaky gut barrier, and an altered intestinal immune response provide a “perfect storm” for the onset of T1D. Importantly, children & adolescents with T1D have high endotoxin serum levels, particularly at disease onset and in genetically predisposed infants, T1D is preceded by a decrease in gut microbiome a-diversity and an increase in inflammatory bacterial species and metabolites. Furthermore, data from the Finnish Diabetic Nephropathy Study show that serum endotoxin contributes to nephropathy in T1D and recent work (in press) has demonstrated that T1D patients have low levels of fecal IAP. Over more than two decades, we and others have established intestinal alkaline phosphatase (IAP) as a potent endogenous anti-inflammatory factor. This enzyme plays a critical role in regard to promoting the gut mucosal barrier, as well as in protecting the host from the detrimental effects related to the gut microbiota. Accordingly, we believe that orally delivered IAP could ameliorate all of the proposed T1D disease mechanisms by: (1) Improving gut barrier function and preventing bacterial translocation, (2) diminishing endotoxemia (and TLR4 activation), and (3) by maintaining a healthy gut microbiome. Our preliminary data provide convincing evidence that IAP could be an effective preventive and/or therapeutic strategy against T1D and its complications. The goals of the proposed project are to perform pre-clinical mechanistic studies that will provide the foundation for moving forward with a clinical trial of IAP in individuals at high-risk for T1D.