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

项目摘要 我们建议建立血友病A分析队列研究计划(HARP)，以支持 用于研究凝血因子VIII(FVIII)的代际精确医学计划的发展 严重血友病A的免疫原性HARP的第一个主要目标是形成一个新的纵向 产前/新生儿/儿童重症血友病研究FVIII抑制剂开发的队列研究。 该队列将包括至少50对母婴，首先是基因携带者母亲，然后是她们的 至少在出生后两年内患有严重血友病A的婴儿。HARP将负责整个 项目协调、行政、数据和生物量管理以及生物统计/数据分析 对该计划的支持。HARP的第二个主要目标是使HARP可共享的开发成为可能 由计划期间收集的经过良好注释的数据和生物样本组成的资源 可通过门户网站、F8portal.org和链接的生物资源库访问。这些资源将提供给 社区研究人员。作为AIM 2的一部分，协议将由HARP协议专家组(PEP)制定 与临床中心联盟联合支持四个HARP科学重点的研究 领域(SEA)：1.孕产妇产前研究，2.围产期研究，3.新生儿/儿科多组学和 免疫学研究，以及4.血友病事件驱动的新生儿/儿科多组学和免疫学研究。 HARP的第三个主要目标是在四个科学领域中的每一个中进行假设检验研究 重点领域。对于母亲产前的SEA，我们将深入刻画母亲FVIII的表达 以及产前环境来验证我们的假设，即母亲的血友病携带者表型调节 通过影响对FVIII耐受蛋白的暴露和婴儿未来出血风险，抑制因子的形成。为 在围产期SEA中，我们假设围产期通过F8基因产物的表达而暴露于FVIII是至关重要的 在调节FVIII免疫反应中的作用，并建议通过新生儿的遗传方法来研究这一点 和母血/脐带血。对于新生儿/儿科组学和免疫学SEA，我们假设 环境、遗传和持续的母体因素促进免疫系统的扰动，导致 一种FVIII免疫反应。我们建议用遗传学、免疫学和--严格研究这些因素 组学评估从新生儿开始，一直持续到生命早期。最后，我们建议调查FVIII 抗体亲和力、表位和多肽呈现来验证我们的假设，即免疫学和/或炎症性 FVIII暴露周围发生的事件影响FVIII-IgG1的产生，并最终影响FVIII-IgG1的抑制物 血友病事件驱动海。总而言之，这项建议寻求提供严格的科学和临床数据 利用生物样品和对公共资源的专家支持来推动创新的研究 FVIII免疫原性。

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.