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Principal Investigator: ROBERT A BRODSKY
Organization: JOHNS HOPKINS UNIVERSITY
Fiscal Year: 2022
Award: $368,356
Funding agency: National Heart Lung and Blood Institute
The overall goal of this competitive renewal is to define the biology of antiphospholipid antibody syndrome,
catastrophic antiphospholipid antibody syndrome and severe forms of COVID-19, and to discover novel
biomarkers and therapeutic targets. Complementopathies are diseases where end-organ damage is driven by
failure to regulate complement on host cells and complement inhibition mitigates cellular and end-organ damage.
Classic examples include paroxysmal nocturnal hemoglobinuria (PNH), atypical hemolytic uremic syndrome
(ahUS), and cold agglutinin disease (CAD). Complementopathies are frequently triggered by inflammation and
are often associated with a severe thrombotic phenotype, often in the microcirculation. A hallmark is the presence
of microthrombi in venules and arterioles due to endothelial injury (thrombotic microangiopathy). Our previously
funded submission entitled, Complementopathies: genotype and phenotype, led to a number of seminal
discoveries. We validated and refined a cell-based assay (modified Ham test, mHam) that measures complement
regulation on human cells, and established the HELLP (hemolysis elevated liver function tests and low platelets)
syndrome, antiphospholipid antibody syndrome (APS), catastrophic antiphospholipid antibody syndrome
(CAPS), and most recently, severe COVID-19 as complementopathies. The mHam was validated because
diseases with a positive mHam were found to have and increase in germline mutations in complement regulatory
genes (aHUS, HELLP), an antibody or protein that activates complement (anti-?2-GPI antibodies, COVID-19) or
both a germline mutation and an antibody (CAPS). Furthermore, we were able to change standard of care for
aHUS by demonstrating that terminal inhibition can be discontinued in most aHUS patients. This proposal is a
natural extension of our previously funded work and seeks to extend this work by addressing many unresolved
questions in the field. Specifically, we will: 1) develop more reliable biomarkers for APS/CAPS by defining which
APS autoantibodies activate complement; 2) identify APS patients who may not require lifelong anticoagulation;
3) prove that germline mutations in complement regulatory genes are common in CAPS; 4) prove that end-organ
damage/microvascular thrombosis/endothelial damage from SARS-CoV-2 infection is due to unregulated activity
of complement; and 5) demonstrate that germline mutations in complement regulatory genes are more common
in patients with more severe forms of COVID19. If funded, we expect to translate our findings into clinical trials
that lead to approved drugs for the treatment of severe APS/CAPS, and COVID19.
Terms: <2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><7S Gamma Globulin><Address><Affect><Alternative Complement Pathway><American Society of Hematology><Anti-Phospholipid Antibody Syndrome><Anti-Phospholipid Syndrome><Antibodies><Anticoagulation><Antiphospholipid Antibody Syndrome><Antiphospholipid Syndrome><Assay><Autoantibodies><Bioassay><Biologic Assays><Biological><Biological Assay><Biological Markers><Biology><Blood Diseases><Blood Platelets><COVID infected patient><COVID patient><COVID positive patient><COVID-19><COVID-19 S protein><COVID-19 infected patient><COVID-19 infection><COVID-19 patient><COVID-19 positive patient><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID19><COVID19 S protein><COVID19 infection><COVID19 patient><COVID19 positive patient><COVID19 spike glycoprotein><COVID19 spike protein><CV-19><CV19><Cell Body><Cells><Clinical Trials><Cold Agglutinin Disease><Cold Hemagglutinin Disease><Complement><Complement 2><Complement 5><Complement Activation><Complement C5><Complement Component 5><Complement Inactivators><Complement Inhibitors><Complement Proteins><Complement component C5><Data><Diagnosis><Disease><Disease remission><Disorder><Drug Therapy><Endothelium><Event><Failure><Familial antiphospholipid syndrome><Frequencies><Funding><Gasser's Syndrome><Genes><Genotype><Germ-Line Mutation><Germline Mutation><Goals><HELLP><HELLP Syndrome><Hematologic Diseases><Hematological Disease><Hematological Disorder><Hemolysis><Hemolysis, Elevated Liver Enzymes, Low Platelet Count><Hemolysis, Elevated Liver Enzymes, Low Platelets><Hemolytic-Uremic Syndrome><Hereditary Mutation><Hughes syndrome><Human><IgG><Immunoglobulin G><Inflammation><Inflammatory><Injury><Laboratories><Laboratory Research><Lead><Liver Function Tests><Marrow platelet><Measures><Microcirculation><Modern Man><Organ><Organ System><Pathogenicity><Patients><Pb element><Pharmacotherapy><Phenotype><Platelets><Properdin Pathway><Proteins><R-Series Research Projects><R01 Mechanism><R01 Program><Recurrence><Recurrent><Regulation><Regulator Genes><Remission><Research><Research Grants><Research Project Grants><Research Projects><SARS Virus><SARS corona virus><SARS coronavirus><SARS-Associated Coronavirus><SARS-CoV><SARS-CoV-1><SARS-CoV-2 S protein><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV2 S protein><SARS-CoV2 infection><SARS-CoV2 spike glycoprotein><SARS-CoV2 spike protein><SARS-Related Coronavirus><Seminal><Severe Acute Respiratory Coronavirus><Severe Acute Respiratory Syndrome Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike 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infected with COVID><patient infected with COVID-19><patient infected with SARS-CoV-2><patient infected with coronavirus disease><patient infected with coronavirus disease 2019><patient infected with severe acute respiratory syndrome coronavirus 2><patient with COVID><patient with COVID-19><patient with COVID19><patient with SARS-CoV-2><patient with coronavirus disease><patient with coronavirus disease 2019><patient with severe acute respiratory distress syndrome coronavirus 2><precision medicine><precision-based medicine><regulatory gene><self reactive antibody><serious COVID><serious COVID-19><serious SARS-CoV-2><serious coronavirus disease><serious coronavirus disease 2019><serious severe acute respiratory syndrome coronavirus 2><severe COVID><severe COVID-19><severe COVID19><severe SARS-CoV-2><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><severe acute respiratory syndrome-CoV><severe coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><standard of care><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic target><thrombotic><thrombotic disease><thrombotic disorder><trans acting element><translation research><translational goal><translational mission><venule>