Complementopathies: Genotype and Phenotype

互补病：基因型和表型

基本信息

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
项目类别：
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

项目摘要

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开发一种个性化的诊断方法和治疗由替代途径驱动病理生理学的人类血液疾病补体 (APC) 是血栓性微血管病 (TMA) 的重要驱动因素。包括非典型溶血性尿毒症综合征 (aHUS)、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（APS）和灾难性抗磷脂抗体对于本提案，我们将这些密切相关的疾病称为调节 APC 的基因中发现了“补体病”。 50% 的患者患有 aHUS，并且在 ptTMA、HELLP 和 APS/CAPS 中也有报道。不幸的是，这些突变的功能后果并不总是清楚的。依库丽单抗的补体抑制对于治疗 aHUS 非常有效，但并未使用由于难以区分 aHUS 和血栓性血小板减少性紫癜，因此常规使用（TTP）并且由于该药物的成本很高（约 600,000 美元），每年有病例报告。目前，依库珠单抗可有效治疗 ptTMA、HELLP 和 APS/CAPS。 HELLP 综合征、APS/CAPS 和 ptTMA 的病理生理学仍然不清楚，并且有最近，我们还没有 FDA 批准的药物来治疗这些往往致命或高发病率的疾病。开发了一种新型血清检测方法，改良的 HAM 检测，具有高度敏感性和特异性用于检测 APC 的全身激活；该测定在区分方面也非常有效；我们还证明了血栓性血小板减少性紫癜（TTP）的 aHUS。如果迅速开始治疗，大多数 aHUS 病例都无需服用依库丽单抗。我们新的初步数据表明 APC 的系统性激活也是 HELLP 综合征、APS/CAPS 和 ptTMA 在这个项目中，我们致力于解决最紧迫的问题。通过以下方式满足补体驱动的 TMA（aHUS、HELLP、APS/CAPS 等）领域的需求： 1) 建立快速诊断；2）预测哪些患者将从补体抑制中受益最多（精准医学）；3）将互补病的基因型和表型联系起来；4）因此，本实验室研究定义了 APS/CAPS 中“无罪与有罪”的自身抗体。项目是假设驱动的、转化的、以目标为导向的。如果成功，我们的提案将开放。 TMA 和潜在的 APS/CAPS 精准医疗之门。