Complementopathies: Genotype and Phenotype

该项目的总体目标是开发个性化的诊断方法， 治疗由旁路途径驱动的病理生理学的人类血液疾病 补体（APC）。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综合征（阿胡斯），移植后TMA（ptTMA），溶血， 肝功能检查升高、低血小板（HELLP）综合征和高凝状态 如抗磷脂抗体综合征（APS）和灾难性抗磷脂抗体 CAPS综合征。在本建议中，我们将这些密切相关的疾病称为 “补体病”调节APC的基因中的种系突变在多达 50%的阿胡斯患者也在ptTMA、HELLP和APS/CAPS中报告。 不幸的是，这些突变的功能后果并不总是清楚的。终端 使用依库珠单抗的补体抑制对于治疗阿胡斯是高度有效的， 由于难以区分阿胡斯和血栓性血小板减少性紫癜， (TTP)而且由于药物的高成本（每年约60万美元）。有病例报告显示 依库珠单抗有效治疗ptTMA、HELLP和APS/CAPS。目前 HELLP综合征、APS/CAPS和ptTMAs的病理生理学仍不清楚， 没有FDA批准的药物来治疗这些通常致命或高度病态的疾病。最近我们 建立了一种新的血清检测方法--改良HAM试验，该试验具有高度的敏感性和特异性 用于检测APC的系统性激活;该测定也高度有效地区分 血栓性血小板减少性紫癜（TTP）的阿胡斯。我们还证明， 如果迅速开始治疗，则在大多数阿胡斯病例中不需要施用依库珠单抗。 我们的新的初步数据表明，APC的系统激活也是细胞凋亡的驱动因素。 HELLP综合征、APS/CAPS和ptTMA。在这个项目中，我们奋进解决最紧迫的问题， 通过以下方式满足补体驱动的TMA（阿胡斯、HELLP、APS/CAPS等）领域的需求：1） 快速诊断; 2）预测哪些患者将从补体抑制中获益最多 （精确医学）; 3）连接补体病的基因型和表型;以及4） 在APS/CAPS中定义“无辜与有罪”自身抗体。因此，本实验室研究 项目是假设驱动的、转化的和目标导向的。如果成功的话，我们的提案将在 为TMA和潜在的APS/CAPS打开了精确医学的大门。

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.