Complementopathies: Genotype and Phenotype

该项目的总体目标是开发一种个性化的方法来诊断和 由替代途径驱动病理生理学的人类血液疾病的治疗 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症综合征(AHUS)、移植后TMAS(PtTMA)、溶血、 肝功能升高、血小板低(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 综合征(CAPS)。在这项提议中，我们将这些密切相关的疾病称为 “互补疗法”。在调节APC的基因中发现胚系突变 50%的aHUS患者还报告了ptTMAs、HELLP和APS/CAPS。 不幸的是，这些突变的功能后果并不总是很清楚。终端 用eculizumab抑制补体治疗aHUS非常有效，但不使用 常规原因是难以区分aHUS和血栓性血小板减少性紫癜 (TTP)，而且由于该药物每年的高成本(约60万美元)。有病例报告说 Eculizumab治疗ptTMAs、HELLP和APS/CAPS有效。目前， HELLP综合征、APS/CAPS和ptTMAS的病理生理学仍不清楚，有 没有FDA批准治疗这些通常是致命或高度病态的疾病的药物。最近，我们 建立了一种新的基于血清的检测方法，改进的Ham试验，该方法具有高度的敏感性和特异性 用于检测APC的系统激活；该分析在区分 血栓性血小板减少性紫癜(TTP)引起的AHUS。我们还证明了这一点 如果迅速开始治疗，在大多数aHUS病例中不需要使用eculizumab。 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ptTMAS。在这个项目中，我们努力解决最紧迫的问题 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；以及4) 在APS/CAPS中定义“无辜与有罪”的自身抗体。因此，本实验室的研究 项目是假设驱动、转换和目标导向的。如果成功，我们的提案将开启 TMA和潜在的APS/CAP的精准医学之门。

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.