A Novel Tolerance Therapeutic for Treating Type Diabetes

Project Summary Our goal is to develop VTC D as a novel tolerance inducing therapeutic for the treatment of Type Diabetes T D T D is an autoimmune disease characterized by the destruction of the insulin producing pancreatic beta cells While the etiology of T D remains undefined evidence suggests that autoimmunity to insulin is a major driver of disease initiation Each year over children and adults are diagnosed with T D worldwide and the incidence is increasing at roughly per year There is no cure for T D Current treatment of T D relies on insulin administration to manage the disease creating a significant need for new therapeutics that treat the underlying cause and prevent the destruction of beta islet cells For successful induction of immune tolerance mucosal tissues play a significant role The epithelial layers that cover the Gut Associated Lymphoid Tissue GALT and Nasopharyngeal Associated Lymphoid Tissue NALT areas contain a subpopulation of specialized cells microfold or M cells which sample environmental antigens and present them to the adjacent immune cells A number of studies now confirm that these cells play a crucial role in the generation of tolerance to a given antigen Reoviruses are segmented double stranded RNA viruses that bind and infect humans via mucosal surfaces using the viral coat protein p We have demonstrated that fusion proteins consisting of p fused to an antigen of choice can bind to M cells and generate a tolerogenic immune response to that antigen The ability of p antigen targeting to induce tolerance has been studied in both allergy and autoimmune models including the mouse EAE model of MS using both oral and intranasal dosing routes These studies demonstrate that p mediated tolerance to the MS auto antigen MOG but not recombinant MOG alone entirely prevents CNS pathology and clinical manifestation of EAE The tolerance response is antigen specific and due to the induction of anti inflammatory cytokines and an increase in suppressive regulatory T cells Tregs The goal of this SBIR application is to develop VTC D as an orally administered tolerance therapeutic for the treatment of newly diagnosed T D patients VTC D is a recombinant protein consisting of p fused to proinsulin This design allows VTC D to exploit p targeting of proinsulin specifically to M cells and to induce tolerance to a broad array of antigenic epitopes within the proinsulin protein The key objectives are to produce sufficient quantities of the VTC D fusion protein demonstrate that oral administration of VTC D inhibits diabetes progression in newly hyperglycemic NOD mice and Determine the pharmacodynamics PD profile of VTC D in NOD mice Successful commercialization of VTC D would ultimately provide a profound front line medical advancement in the treatment and prevention of T D Project Narrative Type Diabetes T D is a T cell mediated autoimmune disease that results in the destruction of the insulin producing pancreatic beta cells More than children and adults are diagnosed with T D worldwide each year a significant number of them children This project aims to develop a novel antigen specific tolerance therapeutic VTC D for the treatment of T D Successful commercialization of VTC D would ultimately provide a profound front line medical advancement in the treatment of T D