title: Potential therapeutic benefit of C1-esterase inhibitor in neuromyelitis optica evaluated in vitro and in an experimental rat model.
abstract: Neuromyelitis optica (NMO) is an autoimmune demyelinating disease of the central nervous system in which binding of anti-aquaporin-4 (AQP4) autoantibodies (NMO-IgG) to astrocytes causes complement-dependent cytotoxicity (CDC) and inflammation resulting in oligodendrocyte and neuronal injury. There is compelling evidence for a central role of complement in NMO pathogenesis. Here, we evaluated the potential of C1-esterase inhibitor (C1-inh) for complement-targeted therapy of NMO. C1-inh is an anti-inflammatory plasma protein with serine protease inhibition activity that has a broad range of biological activities on the contact (kallikrein), coagulation, fibrinolytic and complement systems. C1-inh is approved for therapy of hereditary angioedema (HAE) and has been studied in a small safety trial in acute NMO relapses (NCT 01759602). In vitro assays of NMO-IgG-dependent CDC showed C1-inh inhibition of human and rat complement, but with predicted minimal complement inhibition activity at a dose of 2000 units in humans. Inhibition of complement by C1-inh was potentiated by ∼10-fold by polysulfated macromolecules including heparin and dextran sulfate. In rats, intravenous C1-inh at a dose 30-fold greater than that approved to treat HAE inhibited serum complement activity by <5%, even when supplemented with heparin. Also, high-dose C1-inh did not reduce pathology in a rat model of NMO produced by intracerebral injection of NMO-IgG. Therefore, although C1r and C1s are targets of C1-inh, our in vitro data with human serum and in vivo data in rats suggest that the complement inhibition activity of C1-inh in serum is too low to confer clinical benefit in NMO.
authors.affiliation: Departments of Medicine and Physiology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Lukmanee
authors.initials: L
authors.lastname: Tradtrantip
authors.affiliation: Departments of Medicine and Physiology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Nithi
authors.initials: N
authors.lastname: Asavapanumas
authors.affiliation: Departments of Medicine and Physiology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Puay-Wah
authors.initials: PW
authors.lastname: Phuan
authors.affiliation: Departments of Medicine and Physiology, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: A S
authors.initials: AS
authors.lastname: Verkman
mesh_terms: D000818:Animals; D051401:Aquaporin 4 / Q000276:immunology*; D001253:Astrocytes / Q000187:drug effects / Q000276:immunology*; D001323:Autoantibodies / Q000097:blood; D016466:CHO Cells; D003172:Complement C1 / Q000037:antagonists & inhibitors*; D050718:Complement C1 Inhibitor Protein / Q000008:administration & dosage* / Q000494:pharmacology; D003412:Cricetulus; D016264:Dextran Sulfate / Q000494:pharmacology; D004195:Disease Models, Animal; D004357:Drug Synergism; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D007074:Immunoglobulin G / Q000009:adverse effects / Q000276:immunology; D066298:In Vitro Techniques; D058990:Molecular Targeted Therapy; D009471:Neuromyelitis Optica / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D011917:Rats, Inbred Lew
chemical_list: D051401:Aquaporin 4; D001323:Autoantibodies; D003172:Complement C1; D050718:Complement C1 Inhibitor Protein; D007074:Immunoglobulin G; D006493:Heparin; D016264:Dextran Sulfate