Our goal is to develop VTC-D87 as a novel tolerance-inducing therapeutic for the treatment of Type 1 Diabetes (T1D). T1D is an autoimmune disease characterized by the destruction of the insulin-producing pancreatic beta cells11, 12. While the etiology of T1D remains undefined, evidence suggests that autoimmunity to insulin is a major driver of disease initiation. Each year, over 70,000 children and adults are diagnosed with T1D worldwide, and the incidence is increasing at roughly 3% per year3. There is no cure for T1D. Current treatment of T1D 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 role13-15. 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 cells16, 17. A number of studies now confirm that these cells play a crucial role in the generation of tolerance to a given antigen18-21. Reoviruses are segmented, double- stranded RNA viruses that bind and infect humans via mucosal surfaces using the viral coat protein, p?122, 23. We have demonstrated that fusion proteins consisting of p?1 fused to an antigen of choice can bind to M cells and generate a tolerogenic immune response to that antigen5, 18-21. The ability of p?1-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 routes5, 18, 19, 24. These studies demonstrate that p?1-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)5, 18, 19, 24 The goal of this SBIR application is to develop VTC-D87 as an orally administered, tolerance therapeutic for the treatment of newly diagnosed T1D patients. VTC-D87 is a recombinant protein consisting of p?1 fused to proinsulin. This design allows VTC-D87 to exploit p?1 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: 1) produce sufficient quantities of the VTC-D87 fusion protein; 2) demonstrate that oral administration of VTC-D87 inhibits diabetes progression in newly hyperglycemic NOD mice, and 3) Determine the pharmacodynamics (PD) profile of VTC-D87 in NOD mice. Successful commercialization of VTC-D87 would ultimately provide a profound front-line medical advancement in the treatment and prevention of T1D.
Type 1 Diabetes (T1D) is a T cell-mediated autoimmune disease that results in the destruction of the insulin- producing pancreatic beta cells. More than 70,000 children and adults are diagnosed with T1D worldwide each year, a significant number of them children. This project aims to develop a novel, antigen specific tolerance therapeutic, VTC-D87, for the treatment of T1D. Successful commercialization of VTC-D87 would ultimately provide a profound front-line medical advancement in the treatment of T1D.
