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 开发用于研究凝血因子VIII（FVIII）的代际精准医学计划 严重血友病A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/儿童重度血友病A队列研究FVIII抑制物的形成。 该队列将包括至少50对母婴，首先是遗传携带者母亲，然后是他们的母亲。 患有严重血友病A的婴儿至少在生命的前两年。HARP将负责整个 项目协调、管理、数据和生物标本管理以及生物统计/数据分析 支持该方案。HARP的第二个主要目标是实现HARP可共享的开发。 资源包括在计划过程中收集的注释良好的数据和生物样本 可通过门户网站F8portal.org和链接的生物储存库访问。这些资源将提供给 社区研究员。作为目标2的一部分，HARP协议专家小组（PEP）将制定协议 与临床中心联盟合作，支持HARP四个科学重点领域的研究 地区（东南亚）：1。孕妇产前研究，2。围产期研究，3。新生儿/儿科多组学和 免疫学研究; 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领域进行假设检验研究。 重点领域。对于母亲产前SEA，我们将深入表征母亲的FVIII表达， 和产前环境来检验我们的假设，即母亲的血友病携带者表型调节 通过影响暴露于FVIII耐受性蛋白和婴儿未来出血风险，抑制剂形成。为 在围产期SEA中，我们假设围产期通过F8基因产物表达暴露于FVIII是至关重要的 在调节FVIII免疫反应，并建议通过遗传方法在新生儿中研究这一点， 和母体/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， a FVIII免疫应答。我们建议使用遗传学，免疫学和- 组学评价从新生儿开始并贯穿生命早期。最后，我们建议研究FVIII 抗体亲和力、表位和肽呈递来检验我们的假设， FVIII暴露前后发生的事件影响FVIII-IgG 1的产生，并最终影响 血友病事件驱动SEA。总之，该提案旨在提供严格的科学和临床数据， 生物标本和专家支持的公共资源，以推动创新的调查， 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.