Friday, April 25, 2025
4/25/2025
Development of tolerogenic Factor VIII as immunotherapy to prevent inhibitor development in Hemophilia A - Hemophilia A (HA) is a bleeding disorder caused by deficiency or dysfunction of Factor VIII (FVIII), an important blood coagulation protein. The replacement therapy using exogenous FVIII is the first line of therapy. However, a major clinical complication of this life-saving therapy is the development of neutralizing anti-FVIII antibodies, referred to as inhibitors, that abrogates the biological activity of FVIII and increases the risk of bleeding related morbidity and mortality in HA patients. Current clinical options after inhibitor development are costly (>$700,000 per patient annually) and in some patients, ineffective. Thus, prevention of inhibitor development is cost-effective in terms of patient care but there are no safe and effective preventive therapy currently available to avoid inhibitor development. The overall objective of this application is to develop a tolerogenic form of FVIII (TOLIP-FVIII) as a novel immunotherapy to prevent inhibitor development in HA. This platform technology has been developed with NHLBI support to PI that harnesses the tolerogenic property of our proprietary lysophosphatidylserine (lysoPS) nanoparticle. We observed that an oral and intravenous (IV) pre-administration of FVIII associated with lysoPS effectively reduced inhibitor development in naïve HA mice when challenged with free FVIII, suggesting that FVIII-lysoPS (TOLIP-FVIII) is a tolerogenic form of FVIII that could prevent inhibitor development. As the risk of inhibitor development is much higher during the first 20 exposures of FVIII, we envision this tolerogenic form as beginner replacement therapy during high-risk exposure period, for previously untreated patients (PUPs), to durably prevent inhibitor development. Further, due to improved plasma survival, this could also be a longer acting FVIII for all HA patients. In R61 phase, we propose to (1) develop immunization protocol for durable tolerance; (2) determine the half-life and hemostatic efficacy of IV administered TOLIP-FVIII by conducting pharmacokinetic and pharmacodynamic studies in HA mice and (3) to investigate the toxicity of iv administered TOLIP-FVIII in mice and in non-human primates. These SAs present measurable milestones, identification of optimal immunization/treatment protocol for durable tolerance, non-inferior PK and hemostatic efficacy and acceptable safety profile. As part of R33, in year 3, we will (1) investigate whether this TOLIP-FVIII approach that is successful in HA mice can be translated to HA dogs and (2) characterize PK/PD of this tolerogenic form of FVIII in HA dogs. Collaborations have been established with National Primate Center to investigate toxicity of TOLIP-FVIII in non-human primates and with the University of North Carolina to conduct HA dog studies. We propose a detailed project management plan and partnered with Empire Discovery Institute for R33 phase of the project. Successful completion of the project will lead to a novel immunotherapy platform to prevent inhibitor development in HA and could also lay the foundation for innovative therapeutic options with broad clinical potential, such as prevention of immunogenicity of other therapeutic proteins, improve gene therapy and CRISPR outcomes, and treat autoimmune conditions and allergies.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).