Diabetes mellitus is associated with high morbidity and mortality as well as substantial financial cost. An estimated 1 million Americans have Type I diabetes, and the incidence of disease is approximately 15,000 new cases per year. Both animal models and human studies of autoimmune diabetes have demonstrated that antigen-specific T cells play a significant role in beta cell destruction. The aims of this proposal are to develop and characterize novel human insulin and GAD65 (IG) fusion proteins as reagents to induce antigen- specific T cell tolerance in Type I diabetes. In the Phase I study, we propose to (1) produce and characterize two fusion proteins termed IG2 and IG5, (2) functionally characterize the capacity of the IG2 and IG5 proteins to prevent the onset of type l diabetes in animal models, (3) evaluate the safety of lG fusion proteins, (4) analyze the mechanisms by which IG2 and IG5 proteins induce antigen-specific T cell tolerance in animal models. If this approach proves to be efficacious, we intend to select one of the two proteins as drug candidate in our Phase II proposal to explore the safety and efficacy of an IG protein treatment in the prevention of diabetes as well the treatment of new onset diabetic patients in Phase I clinical trials. Given the potential number of patients who could potentially benefit from a therapeutic agent that specifically blocks beta cell damage during autoimmune diabetes, the market for such a product represents a significant commercial opportunity. PROPOSED COMMERCIAL APPLICATIONS: Since approximately 1 million Americans have Type I diabetes, a pharmaceutical product capable of blocking beta cell damage during diabetes would be clinically significant, and address pharmaco-economic concerns.
