Complementopathies: Genotype and Phenotype

互补病：基因型和表型

• 批准号: 9284289
• 负责人: ROBERT A BRODSKY
• 金额: $ 40.5万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9284289
• 关键词: Alternative Complement Pathway; Antibodies; Antiphospholipid Syndrome; Autoantibodies; Biological Assay; Blood Platelets; Case Study; Cleaved cell; Complement; Complement 3 Convertase; Complement 3b; Complement Activation; Complement Factor H; Complement Inactivators; Data; Diagnosis; Disease; Drug Costs; FDA approved; Fibrinogen; Functional disorder; Generations; Genes; Genotype; Germ-Line Mutation; Goals; HELLP Syndrome; Hematological Disease; Hematopoietic; Hemolysis; Hemolytic-Uremic Syndrome; Human; Institutes; Laboratories; Laboratory Research; Lead; Link; Liver Function Tests; Lupus Coagulation Inhibitor; Mutation; Pathogenicity; Patients; Pharmaceutical Preparations; Phenotype; Reporting; Research Project Grants; Serum; Syndrome; Testing; Thrombophilia; Thrombotic Thrombocytopenic Purpura; Transplantation; adverse outcome; alternative pathway complement C3 convertase; anti-IgG; base; complement 3 regulator; diagnostic assay; fetal; improved; novel; novel diagnostics; personalized approach; precision medicine; rapid diagnosis; response

The overall goal of this project is to develop a personalized approach to the diagnosis and treatment of human blood diseases where pathophysiology is driven by the alternative pathway of complement (APC). The APC is an important driver of thrombotic microangiopathies (TMA) including atypical hemolytic uremic syndrome (aHUS), post-transplant TMAs (ptTMA), hemolysis, elevated liver function tests, and low platelets (HELLP) syndrome and hypercoagulable states such as antiphospholipid antibody syndrome (APS) and catastrophic antiphospholipid antibody syndrome (CAPS). For this proposal we refer to these closely related diseases as “complementopathies”. Germline mutations in the genes that regulate the APC are found in up to 50% of patients with aHUS and have also been reported in ptTMAs, HELLP, and APS/CAPS. Unfortunately, the functional consequence of these mutations is not always clear. Terminal complement inhibition with eculizumab is highly effective for treating aHUS but is not used routinely because of difficulty in distinguishing aHUS and thrombotic thrombocytopenic purpura (TTP) and because of the high cost of the drug (~$600,000) annually. There are case reports of eculizumab being effective in treating ptTMAs, HELLP, and APS/CAPS. Currently, the pathophysiology of HELLP syndrome, APS/CAPS, and ptTMAs remains obscure and there are no FDA approved drugs to treat these often fatal or highly morbid diseases. Recently, we developed a novel serum based assay, modified HAM test, which is highly sensitive and specific for detecting systemic activation of the APC; the assay is also highly effective in distinguishing aHUS from thrombotic thrombocytopenic purpura (TTP). We also demonstrate that continued administration of eculizumab is unnecessary in most aHUS cases if therapy is instituted rapidly. Our new preliminary data demonstrate that systemic activation of the APC is also a driver of the HELLP syndrome, APS/CAPS and ptTMAs. In this project we endeavor to solve the most pressing needs in the field of complement-driven TMAs (aHUS, HELLP, APS/CAPS etc) by: 1) establishing a rapid diagnosis; 2) predicting which patients will benefit most from complement inhibition (precision medicine); 3) linking the genotype and phenotype of complementopathies; and 4) defining “innocent versus guilty” autoantibodies in APS/CAPS. Therefore, this laboratory research project is hypothesis-driven, translational, and goal-oriented. If successful, our proposal will open the door to precision medicine for TMAs and potentially APS/CAPS.

该项目的总体目标是为诊断和 替代途径驱动病理生理学的人类血液疾病的治疗 完成（APC）。 APC是血栓形成微型疾病（TMA）的重要驱动力 包括非典型溶血性尿毒综合征（AHU），移植后TMA（PTTMA），溶血， 肝功能测试升高，低血小板（HELLP）综合征和高凝状态 例如抗磷脂抗体综合征（AP）和灾难性的抗磷脂抗体 综合征（上限）。对于此提案，我们将这些密切相关的疾病称为 “互补病”。发现调节APC的基因中的种系突变在 50％的AHU患者在PTTMA，HELLP和APS/CAP中也有报道。 不幸的是，这些突变的功能后果并不总是很清楚。终端 与eculizumab的补体抑制作用非常有效地治疗ahus，但不使用 通常是因为难以区分AHUS和血栓性血小板减少紫红色 （TTP），由于该药物的高成本（约60万美元）。有案例报告 Eculizumab有效地治疗PTTMA，HELLP和APS/CAPS。目前， HELLP综合征，APS/CAPS和PTTMA的病理生理学仍然晦涩难懂，并且有 没有FDA批准治疗这些经常致命或高病态疾病的药物。最近，我们 开发了一种新型基于血清的测定，修饰的HAM测试，该测试高度敏感且具有特异性 用于检测APC的全身激活；该测定在区分方面也非常有效 血栓性血小板减少紫红色（TTP）的痤疮。我们还证明了继续 如果迅速进行治疗，则在大多数AHUS病例中不必进行eculizumab的给药。 我们的新初步数据表明，APC的全身激活也是 HELLP综合征，AP/CAPS和PTTMA。在这个项目中，我们努力解决最紧迫的 在补充驱动的TMA（Ahus，Hellp，APS/CAPS等）领域的需求：1）建立 快速诊断； 2）预测哪些患者将从完成抑制中受益最大 （精密医学）； 3）连接互补路的基因型和表型；和4） 在APS/CAPS中定义“无辜与有罪”自身抗体。因此，这项实验室研究 项目是由假设驱动的，翻译和面向目标的。如果成功，我们的建议将开放 TMA和潜在的AP/CAP的精密药物的门。