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治疗的主要手段。这项名为“血友病生物学变异”的TRC-THD U54应用，旨在提高我们对严重血友病A人群中抑制剂发展和表型异质性潜在基础的理解。此外，它还提出了将基础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，以测试预测严重血友病a出血品质的新诊断方法。fVIII替代疗法最可怕的并发症是fVIII抑制抗体（抑制剂）的发展，约30%的严重和中度血友病a患者出现这种情况。fVIII抑制剂可在非血友病患者中发生，产生一种称为获得性血友病A的自身免疫性疾病。获得性血友病A是最常见的涉及凝血系统的自身免疫性出血性疾病。获得性血友病患者经常出现严重的、危及生命或肢体的出血，难以控制。A型血友病患者要么接受按需治疗以控制出血发作，要么接受预防性治疗以防止出血。为了限制发展为致残性关节病的可能性，大多数患者接受预防性治疗。然而，提供预防性治疗所需的输液频率往往导致依从性差。因此，在美国，许多a型血友病患者接受按需治疗。预防性治疗非常昂贵，给社会造成了经济负担。严重血友病A是由fVIII活性测定确定的，其水平低于正常值的1%，通常在血液中诊断