Nanoparticles for Immune Tolerance to FVIII

DESCRIPTION provided by applicant A major problem in the treatment of hemophilia A patients with factor VIIII FVIII is that up to of these patients produce antibodies to therapeutic FVIII These antibodies block inhibit the pro coagulant function of FVIII and thus are termed andquot inhibitorsandquot The focus of Selecta Biosciences and the Scott lab has been to develop novel approaches for the induction of tolerance so that it can be applied to the prevention or reversal of undesirable immune responses including the formation of hemophilia inhibitors Selecta has pioneered the use for virus like biodegradable nanoparticles NP based on materials that are FDA approved namely PLGA poly lactic co glycolic acid particles that have been in clinical use for more than years This nanoparticle delivery system can be used to either vaccinate or tolerize a specific immune response focusing recently on antigen specific immune tolerance for therapeutic and prophylactic applications Selectaandapos s proprietary technology platform is based on innovations in nanotechnology and immunology discovered at MIT and Harvard Medical School In the case of hemophilia A the delivery method involves nanoparticle delivery of FVIII or its constituent immunodominant peptides with approved immunosuppressive drugs such as rapamycin in PLGA NP Based on preliminary success with the Selecta nanoparticles with cognate antigens as well as in our hemophilia model we will to further this novel approach for tolerance to translation and clinical trial The aims of this STTR proposal are to determine the minimal requirements for tolerance induction to FVIII with Selecta nanoparticle formulations to further understand the mechanism of nanoparticle induced tolerance and finally to develop evidence for human translation using an in vitro system with human dendritic cells and T cell clones These studies should further our translation of these novel tolerogenic NP products to a clinical trial PUBLIC HEALTH RELEVANCE Hemophilia A is a life threatening blood clotting disorder caused by mutations in factor VIII a clotting factor The current therapy for this disorder is to administer functional factor VIII intravenously but a significant number of patients produce antibodies to the treatment making it ineffective Our goal is to develop and translate novel therapeutic protocols to prevent and reverse this undesirable antibody formation by using immune modulatory nanoparticles developed by Selecta to induce tolerance to therapeutic factor VIII