Unraveling the immune response to factor VIII

揭示对因子 VIII 的免疫反应

• 批准号: 9522256
• 负责人: John S. Lollar
• 金额: $ 164.03万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9522256
• 关键词: Address; Antibodies; Antigen-Antibody Complex; Behavior; Biomedical Engineering; Blood Coagulation Disorders; Blood coagulation; Caring; Complication; Computer Simulation; Deuterium; Development; Doctor of Philosophy; Electron Microscopy; Epitopes; F8 gene; Factor VIII; Future; Genetic; Glycobiology; Goals; Hemophilia A; Hemorrhage; Human; Hydrogen; Immune; Immune response; Immunobiology; Immunologics; Immunology; Infusion procedures; Intravenous infusion procedures; Lead; Lesion; Liver; Mass Spectrum Analysis; Methods; Molecular; Mutation; Negative Staining; Outcome; Patients; Plasma; Polysaccharides; Prevention; Proteins; Protocols documentation; Recombinants; Research; Research Personnel; Roentgen Rays; Role; Spectrum Analysis; Structure; Surface Plasmon Resonance; Technology; Transgenes; Treatment Factor; X Chromosome; X-Ray Crystallography; analytical ultracentrifugation; antibody inhibitor; design; gene therapy; immunogenic; immunogenicity; immunopharmacology; improved; inhibitor/antagonist; interest; microbiota; novel; particle; patient population; pre-clinical; prevent; programs; protein structure; recombinant antihemophilic factor VIII; reconstruction; response; sedimentation velocity; skills; standard of care; structural biology

Overall Component Project Summary/Abstract Hemophilia A is the most common severe congenital bleeding disorder. It is caused by mutations in the F8 gene on the X chromosome that lead to deficiency or complete absence of blood coagulation factor VIII (fVIII). Current management of patients with hemophilia is intravenous infusion of either plasma-derived or recombinant fVIII to prevent bleeding or to treat bleeding after it has occurred. The most significant complication in the management of patients with hemophilia A is the development of inhibitory antibodies (inhibitors) to fVIII. The future standard- of-care of hemophilia A will be gene therapy. In preclinical gene therapy studies, the development of inhibitors has prevented long-term correction of the genetic lesion. We propose to create an Emory Factor VIII Center consisting of a group of highly interactive investigators with diverse research skills and an established interest in the immunogenicity of fVIII. The central hypothesis is that structural determinants in fVIII structure, including its glycans, are responsible for its highly immunogenic behavior. The three projects in this proposal address these themes with aims to determine the relationship of fVIII structure, fVIII glycobiology and fVIII in gene therapy settings to its immunogenicity. In Project 1, “The Structural Basis for Immune Recognition of Factor VIII”, we seek to identify immunogenic structures that can be modified to produce a less immunogenic fVIII molecule. This will be accomplished by using X-ray crystallography, hydrogen-deuterium exchange mass spectrometry, single-particle negative-stain electron microscopy, surface plasmon resonance spectroscopy and analytical ultracentrifugation to determine the structure of fVIII and fVIII immune complexes. In Project 2, “The Immunobiology of Factor VIII”, the role of fVIII glycans and the impact of microbiota on anti-αGal antibody development on inhibitor formation will be determined. Additionally, the immunogenicity of fVIII immune complexes characterized in Project 1 will be evaluated. In Project 3, “Novel Factor VIII Technologies for the Prevention or Treatment of Factor VIII Inhibitors”, the molecular composition and immune reactivity of bioengineered recombinant infusion products as well as liver-directed AAV and HSC- directed LV gene therapy derived fVIII will be analyzed. Critical design parameters associated with immunogenicity and inhibitor eradiation potential of liver-directed AAV-fVIII gene therapy will be identified. Additionally, the immunogenicity and inhibitor eradicating potential of non-genotoxic HSC-directed LV gene therapy protocols will be evaluated. This program is highly significant because it addresses causal mechanisms for fVIII inhibition and implications for modifying these mechanisms to improve therapy for hemophilia A patients.

整体组件 项目摘要/摘要 血友病A是最常见的严重先天性出血性疾病。它是由F8基因突变引起的 X染色体上导致凝血因子VIII(FVIII)缺乏或完全缺失的基因。当前 血友病患者的治疗是静脉输注血浆衍生或重组FVIII 防止出血或在出血发生后进行治疗。管理中最重要的复杂因素 血友病A患者的主要症状是对FVIII产生抑制性抗体(抑制物)。未来的标准- 对血友病A的护理将是基因治疗。在临床前基因治疗研究中，抑制剂的发展 阻碍了基因损伤的长期纠正。 我们建议创建一个埃默里第八因子中心，由一组高度互动的调查人员组成， 不同的研究技能和对FVIII免疫原性的既定兴趣。中心假设是 FVIII结构中的结构决定因素，包括其多聚糖，是其高度免疫原性的原因 行为。本提案中的三个项目涉及这些主题，目的是确定 FVIII结构、FVIII糖生物学和FVIII在基因治疗环境中对其免疫原性的影响。在项目1中，“The 第八因子免疫识别的结构基础“，我们试图确定免疫原性结构，可以 经修饰后产生免疫原性较低的FVIII分子。这将通过使用X射线结晶学来实现， 氢-氚交换质谱仪，单粒子负染色电子显微镜，表面 等离子体共振光谱和分析超速离心法测定FVIII和FVIII的结构 免疫复合体。在项目2“因子VIII的免疫生物学”中，FVIII多糖的作用和因子VIII的影响 微生物区系对抗α半乳糖抗体形成的抑制作用将被确定。此外， 将对项目1中描述的FVIII免疫复合物的免疫原性进行评估。项目3，“小说” 因子防治因子抑制剂的技术“，分子组成 和免疫反应性的生物工程重组输液产品以及肝脏导向的AAV和HSC- FVIII衍生的定向LV基因治疗将被分析。与以下各项相关的关键设计参数 肝脏导向AAV-FVIII基因治疗的免疫原性和抑制物辐射潜力将得到鉴定。 此外，非遗传毒性HSC导向的LV基因的免疫原性和抑制物清除潜力 治疗方案将进行评估。这个程序非常有意义，因为它解决了因果机制 对于FVIII的抑制以及修改这些机制以改善血友病A患者治疗的意义。