Complementopathies: Genotype and Phenotype

这个项目的总体目标是开发一种个性化的诊断方法

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.