A Severe Hemophilia A Intergenerational Cohort Research Program for the Study of Factor VIII Immunogenicity

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Project Summary We propose to establish a Hemophilia A Analytical Cohort Research Program (HARP) to support the development of an Intergenerational Precision Medicine Program for the study of factor VIII (FVIII) immunogenicity in severe hemophilia A. The first major aim of HARP is to form a new longitudinal antenatal/neonatal/pediatric severe hemophilia A cohort to study the development of FVIII inhibitors. The cohort will encompass at least 50 mother-baby pairs, following first genetic carrier mothers and then their babies with severe hemophilia A over at least the first two years of life. HARP will be responsible for the overall project coordination, administration, data and biospecimen management, and biostatistics/data analytical support for the program. The second major aim of HARP is to enable the development of the HARP Shareable Resource comprised of well annotated data and biological samples collected over the course of the program accessible through a portal, F8portal.org and a linked biorepository. These resources will be made available to community researchers. As part of aim 2, protocols will be developed by the HARP Protocols Expert Panel (PEP) in conjunction with the Consortium of Clinical Centers to support research in four HARP Scientific Emphasis Areas (SEAs): 1. maternal antenatal research, 2. perinatal research, 3. neonatal/pediatric multi-omics and immunology research, and 4. hemophilia-event driven neonatal/pediatric multi-omics and immunology research. The third major aim of HARP is to perform hypothesis-testing research in each of the four Scientific Emphasis Areas. For the maternal antenatal SEA, we will deeply characterize the mother's expression of FVIII and the antenatal environment to test our hypothesis that the mother's hemophilia carrier phenotype modulates inhibitor development by influencing exposure to FVIII tolerizing proteins and future bleeding risk of infant. For the perinatal SEA, we hypothesize that perinatal exposure to FVIII via expression of F8 gene products are critical in modulating the FVIII immune response and propose to investigate this via genetic methods in the neonate and maternal/cord blood. For the neonatal/pediatric -omics and immunology SEA, we hypothesize that environmental, genetic, and persistent maternal factors promote perturbations in the immune system leading to a FVIII immune response. We propose to rigorously investigate these factors using genetic, immunologic and - omics evaluation beginning in neonates and following through early life. Finally, we propose to investigate FVIII antibody affinity, epitope, and peptide presentation to test our hypothesis that immunologic and/or inflammatory events occurring around FVIII exposure influence production of FVIII-IgG1 and ultimately inhibitors for the hemophilia event-driven SEA. Together, this proposal seeks to provide rigorous scientific and clinical data with biospecimens and expert support for a communal resource to drive innovative investigations of FVIII immunogenicity.