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

严重血友病 因子 VIII 免疫原性研究的代际队列研究计划

• 批准号: 10512711
• 负责人: Jill Marie Johnsen
• 金额: $ 179.19万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-21 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10512711
• 关键词: Address; Alleles; Antibodies; Antibody Affinity; Area; B-Lymphocytes; Biological; Biological Assay; Biometry; Cells; Child; Childhood; Clinical; Clinical Data; Clonal Expansion; Communication; Communities; Community Networks; Consensus; Coupled; Data; Data Analyses; Data Analytics; Data Collection; Data Set; Development; Enrollment; Environment; Environmental Risk Factor; Epitope Mapping; Epitopes; Evaluation; Event; Exposure to; F8 gene; Factor VIII; Functional disorder; Future; Genes; Genetic; Genetic Carriers; Genotype; Hemophilia A; Hemorrhage; IgG1; Immune; Immune response; Immune system; Immunologics; Immunology; Infant; Inflammatory; Inherited; Investigation; Kinetics; Knowledge; Life; Link; Logistics; Methods; Microchimerism; Monitor; Mothers; Neonatal; Outcome; Patients; Peptides; Perinatal; Perinatal Exposure; Phenotype; Production; Productivity; Program Accessibility; Proteins; Protocols documentation; Research; Research Personnel; Research Support; Resource Sharing; Resources; Risk; Sampling; Specimen; Statistical Methods; System; Testing; Time; Umbilical Cord Blood; Variant; Work; antenatal; biobank; clinical center; cohort; commune; computing resources; data harmonization; data sharing; design; falls; fetal; flexibility; gene product; genetic counselor; immunogenicity; implementation barriers; inhibitor; innovation; intergenerational; multiple omics; neonate; offspring; participant safety; pilot test; precision medicine; programs; recruit; repository; sample collection; trial design

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.

项目概要 我们建议建立血友病 A 分析队列研究计划 (HARP) 以支持 开发用于研究因子 VIII (FVIII) 的代际精准医学计划 严重血友病 A 中的免疫原性。HARP 的首要目标是形成新的纵向 产前/新生儿/儿童严重血友病 研究 FVIII 抑制剂开发的队列。 该队列将包含至少 50 对母婴，首先是遗传携带者母亲，然后是她们的母亲 至少在生命的头两年患有严重 A 型血友病的婴儿。 HARP将负责整体 项目协调、行政、数据和生物样本管理以及生物统计/数据分析 对计划的支持。 HARP 的第二个主要目标是促进 HARP Shareable 的开发 资源由在计划过程中收集的注释良好的数据和生物样本组成 可通过门户网站 F8portal.org 和链接的生物存储库进行访问。这些资源将提供给 社区研究人员。作为目标 2 的一部分，协议将由 HARP 协议专家小组 (PEP) 开发 与临床中心联盟合作支持四个 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领域进行假设检验研究 重点领域。对于产妇产前SEA，我们将深入表征母亲FVIII的表达 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 FVIII 耐受蛋白的暴露和婴儿未来出血风险来开发抑制剂。为了 围产期 SEA，我们假设围产期通过 F8 基因产物表达接触 FVIII 至关重要 调节 FVIII 免疫反应，并建议通过新生儿遗传方法对此进行研究 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会促进免疫系统的扰动，从而导致 FVIII 免疫反应。我们建议使用遗传、免疫学和 - 严格研究这些因素 从新生儿开始并贯穿生命早期的组学评估。最后，我们建议调查FVIII 抗体亲和力、表位和肽呈递来检验我们的假设，即免疫学和/或炎症 FVIII 暴露周围发生的事件会影响 FVIII-IgG1 的产生以及最终的抑制剂 血友病事件驱动的策略性环境评估。该提案旨在共同提供严格的科学和临床数据 通过生物样本和专家对公共资源的支持来推动创新研究 FVIII 免疫原性。