Biological Variation in Hemophilia

血友病的生物学变异

• 批准号: 8464228
• 负责人: John S. Lollar
• 金额: $ 231.64万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8464228
• 关键词: A Mouse; Adrenoleukodystrophy; Adult; Ally; Animal Model; Antibodies; Antigen Presentation; Autoimmune Process; Award; B-Lymphocytes; Basic Science; Binding; Biological; Biological Assay; Blood Coagulation Factor; Blood Platelets; Breeding; Bypass; Cancer Center; Caring; Clinical; Clinical Research; Clinical Sciences; Coagulation Process; Collaborations; Complication; Congenital Disorders; DAG/PE-Binding Domain; Data; Databases; Developed Countries; Development; Diagnosis; Diagnostic; Diagnostic tests; Disease; Disease susceptibility; Doctor of Medicine; Doctor of Philosophy; Economic Burden; Engraftment; Environment; Epitopes; Evolution; Faculty; Family suidae; Fibrin; Frequencies; Future; Generations; Genotype; Hematological Disease; Hematopoietic stem cells; Hemophilia A; Hemorrhage; Hemostatic Agents; Hemostatic function; Heterogeneity; Human; Human Resources; Hybrids; Immune response; In Vitro; Individual; Informatics; Infusion procedures; Institutes; Institution; Joints; Laboratories; Laboratory Research; Life; Limb structure; Membrane; Memory; Methods; Microfluidics; Modeling; Molecular; Monoclonal Antibodies; Mus; Patients; Phenotype; Phospholipids; Physicians; Plasma; Population; Pre-Clinical Model; Principal Investigator; Process; Prophylactic treatment; Reagent; Recovery; Regimen; Replacement Therapy; Research; Research Personnel; Research Project Grants; Research Training; Role; Scientist; Services; Severe Combined Immunodeficiency; Societies; Specimen; Structure; System; Testing; Thrombin; Thrombosis; Time; Training; Translating; Translational Research; Trauma; United States; United States National Institutes of Health; Universities; Variant; Work; arthropathies; base; biobank; conditioning; design; disease phenotype; factor IXa-factor VIIIa; gene therapy; human subject; improved; in vivo Model; infancy; inhibitor/antagonist; meetings; multidisciplinary; next generation; novel; novel diagnostics; novel strategies; preclinical study; prevent; programs; prophylactic; prospective; response; skills; symposium; treatment center; von Willebrand Factor; web site

FVIII (fVIII) replacement therapy is the mainstay of the management of congenital hemophilia A in developed countries. This TRC-THD U54 application, entitled Biological Variation in Hemophilia, seeks to improve our understanding of inhibitor development and the underlying basis for phenotypic heterogeneity in the severe hemophilia A population. Additionally, it proposes novel approaches to translate basic discovery into preclinical models of inhibitor treatment and into clinical studies to test novel diagnostics predictive of the bleeding diathesis n severe hemophilia A. The most dreaded complication of fVIII replacement therapy is the development of inhibitory antibodies to fVIII (inhibitors), which occur in approximately 30% of individuals with severe and moderately severe hemophilia A. Additionally, fVIII inhibitors can occur in nonhemophiliacs, producing an autoimmune condition called acquired hemophilia A. Acquired hemophilia A is the most common autoimmune bleeding disorder involving the coagulation system. Patients with acquired hemophilia frequently present with severe, life- or limb-threatening bleeding that is difficult to manage. Individuals with hemophilia A are treated either with on-demand therapy to manage bleeding episodes or with prophylactic therapy to prevent bleeding. To limit the potential for the development of crippling arthropathy most patients receive prophylactic therapy. However, the frequency of infusions required to deliver prophylactic therapy frequently results in poor compliance. As a result, many individuals with hemophilia A in the United States are treated with on-demand therapy. Prophylactic therapy is very expensive, creating an economic burden to society. Severe hemophilia A, which is defined by a fVIII activity assay in which the level is less than 1% of normal, usually is diagnosed in the first year of life. Individuals with severe hemophilia A often have spontaneous bleeding, i.e., bleeding in the absence of overt trauma. However, there is considerable variability in the bleeding diathesis within the severe hemophilia A population. Currently, there are no diagnostic tests that can predict variability of bleeding. Identification of such diagnostics would guide the management of individuals with severe hemophilia A in early life, e.g., by identifying individuals in whom prophylaxis should be aggressively pursued to protect target joints. Even the best current situation, namely successful prophylactic therapy in an individual with congenital hemophilia A who is not inhibitor prone, does not represent a cure. Gene therapy continues to represent the best chance for cure of hemophilia A. Advances in hematopoietic stem cell (HSC)-based gene therapy for other congenital disorders, including adrenoleukodystrophy and severe combined immunodeficiency disease, and preclinical studies in a murine hemophilia A model at Emory University, suggest that a cure for hemophilia A, including inhibitor patients, is imminent. State-of-the-art management of hemophilia occurs in multidisciplinary treatment centers. The care of individuals with hemophilia from infancy through adult life requires a team of physicians and allied personnel to manage the evolution of issues that arise. Additionally, a hemophilia treatment center ideally includes an integrated basic, translational and clinical research program to provide ongoing advances in the management of hemophilia. There is an unmet need for more physician scientists to provide the specialized care and conduct research in hemophilia treatment centers. The investigators in this project are physician-scientists, clinical investigatos and molecular biologists in the Hemostasis/Thrombosis Program in the Aflac Cancer Center & Blood Disorders Service at Emory University who have broad expertise in hemophilia care and hemophilia research. The program represents a fertile environment for training the next generation of physician-scientists, clinical, and basic researcher in the management and research of hemostatic disorders

FVIII（FVIII）替代疗法是发达国家先天性血友病A的支柱。这种标题为血友病的生物学变异的TRC-THD U54旨在提高我们对抑制剂发展的理解以及严重血友病A种群中表型异质性的基本基础。另外，它提出了将基本发现转化为抑制剂治疗的临床前模型和临床研究的新方法，以测试对临床症状的诊断，可预测出血性临床n严重的血友病A. FVIII替换疗法最恐惧的并发症是抑制性抗体对fviii A.的抑制性抗体的发展，该抑制作用（抑制剂均为抑制剂），这是抑制作用的30％。此外，非生物友善可能会发生FVIII抑制剂，该抑制剂产生一种自身免疫性疾病，称为获得性血友病A.获得的血友病A是涉及凝结系统的最常见的自身免疫性出血疾病。获得性血友病的患者经常出现严重，生命或肢体威胁性出血的患者。血友病A的患者接受按需治疗以管理出血事件或预防性疗法以防止出血。为了限制发育的潜力，大多数患者接受预防性疗法。但是，提供预防治疗所需的输注频率通常会导致依从性差。结果，美国许多血友病A的患者接受了按需治疗的治疗。预防性疗法非常昂贵，给社会带来了经济负担。严重的血友病A是由FVIII活性测定法定的，其中水平小于正常水平的1％，通常在 生命的第一年。严重的血友病患者经常会自发出血，即在没有明显创伤的情况下出血。但是，严重的血友病人群中的出血素质存在很大的差异。当前，没有诊断测试可以预测出血的变异性。这种诊断的识别将指导早年患有严重血友病A的个体的管理，例如，通过确定应积极追求预防的人来保护目标关节。即使是当前的最佳状况，即在不容易发生抑制剂的先天性血友病A中成功的预防性治疗也不代表治愈方法。基因疗法继续代表治愈血友病的最佳机会A.造血性干细胞（HSC）基于基于其他先天性疾病的基因疗法，包括肾上腺素肌营养不良症和严重的免疫缺陷疾病，以及在默里大学的鼠血液友善患者中，cure insmoplia insmoplia insmoplia insmophia insmoplia insmoplia insmoplia insmophia insmophia insmophia insmophia insmollia，血友病的最新治疗发生在多学科治疗中心。从婴儿期到成年生活的血友病患者的照顾需要一组医生和盟友的人来管理出现的问题的演变。此外，理想情况下，血友病治疗中心包括一项综合，转化和临床研究计划，以提供血友病治疗的持续进展。不满足更多医师科学家在血友病治疗中心提供专业护理和进行研究的需求。该项目的研究人员是医师科学家，临床研究和分子生物学家在埃默里大学Aflac癌症中心和血液疾病服务中的止血/血栓形成计划中，他们在血友病和血友病研究方面具有广泛的专业知识。该计划代表了一个肥沃的环境，用于培训下一代医师科学家，临床和基础研究人员的止血性疾病的管理和研究