A Novel Tolerance Therapeutic for Treating Graves' Disease

Project Summary Our goal is to develop VTC Gas a novel tolerance inducing therapeutic to treat GravesDiseaseGDGD is an autoimmune disease in which patients produce an antibody that binds to the thyroid stimulating hormone receptorTSHRmimicking the effects of thyroid stimulating hormoneTSHAutoimmune induced hyperthyroidism is inducedresulting in a wide range of symptoms such as thyroid enlargementgoitermuscle weaknessatrial fibrillation due to increased heart rate leading to strokeand blindness due to progressive GravesopthalmopathyFor successful induction of immune tolerancemucosal tissues play a significant roleThe epithelial layers that cover the Gut Associated Lymphoid TissueGALTand Nasopharyngeal Associated Lymphoid TissueNALTareas contain a subpopulation of specialized cellsmicrofold or M cellsthat sample environmental antigens and present them to the adjacent immune cellsSeveral studies now confirm these cells play a crucial role in the generation of tolerance to a given antigenReoviruses are segmenteddouble stranded RNA viruses that bind and infect humans via mucosal surfaces using the viral coat proteinpWe have demonstrated that fusion proteinsconsisting of pfused to an antigen of choicecan bind to M cells and generate a tolerogenic immune response to that antigenThe ability of pantigen targeting to induce tolerance has been studied in both allergy and autoimmune modelsusing both oral and intranasal dosing routesFor instancepmediated tolerance to the MS autoantigenMOGbut not recombinant MOG aloneprevents CNS pathology and clinical manifestation of experimental autoimmune encephalitisEAEin miceThe tolerance response is antigen specificand is due to the induction of anti inflammatory cytokines and an increase in suppressive regulatory T cellsTregsand regulatory B cellsBregsThe goal of this Fast track SBIR application is to develop VTC Gas an orally administeredtolerance therapeutic for the treatment of GDVTC Gis a recombinant protein consisting of pfused to the antigenic region of TSHRThis design allows VTC Gto exploit ptargeting of the auto antigen specifically to M cellsand to induce tolerance to the known antigenic region of the TSHRSuccessful completion of this proposal will create a first in class tolerance therapeutic for newly diagnosed GD patientsThe high level objectives are toestablish VTC Gproduction and analytical assays to support manufacturingpurificationbioactivity determinationand formulationdefine the IND enabling studies to support our clinical study designanddevelop non GLP and GLP preclinical datasets to help us obtain FDA IND approvalSuccessful commercialization of VTC Gwould ultimately provide a profound front line medical advancement in the treatment of GD Project Narrative Gravesdisease is an autoimmune disease in which patients produce an antibody that mimics the effects of thyroid stimulating hormoneTSHresulting in autoimmune induced hyperthyroidismThis project aims to develop a novelantigen specific tolerance therapeuticVTC Gfor the treatment of GD in newly diagnosed patientsVTC Gis expected to rapidly induce long term tolerance and sustained anti TSH receptor antibody reduction following low doseoral treatmentSuccessful commercialization of VTC Gwould ultimately provide a profound front line medical advancement in the treatment of GD