title: Treatment of neuromyelitis optica: state-of-the-art and emerging therapies.
abstract: Neuromyelitis optica (NMO) is an autoimmune disease of the CNS that is characterized by inflammatory demyelinating lesions in the spinal cord and optic nerve, potentially leading to paralysis and blindness. NMO can usually be distinguished from multiple sclerosis (MS) on the basis of seropositivity for IgG antibodies against the astrocytic water channel aquaporin-4 (AQP4). Differentiation from MS is crucial, because some MS treatments can exacerbate NMO. NMO pathogenesis involves AQP4-IgG antibody binding to astrocytic AQP4, which causes complement-dependent cytotoxicity and secondary inflammation with granulocyte and macrophage infiltration, blood-brain barrier disruption and oligodendrocyte injury. Current NMO treatments include general immunosuppressive agents, B-cell depletion, and plasma exchange. Therapeutic strategies targeting complement proteins, the IL-6 receptor, neutrophils, eosinophils and CD19--all initially developed for other indications--are under clinical evaluation for repurposing for NMO. Therapies in the preclinical phase include AQP4-blocking antibodies and AQP4-IgG enzymatic inactivation. Additional, albeit currently theoretical, treatment options include reduction of AQP4 expression, disruption of AQP4 orthogonal arrays, enhancement of complement inhibitor expression, restoration of the blood-brain barrier, and induction of immune tolerance. Despite the many therapeutic options in NMO, no controlled clinical trials in patients with this condition have been conducted to date.
authors.affiliation: Academic Neurosurgery Unit, St George's, University of London, Room 0.136 Jenner Wing, Cranmer Terrace, Tooting, London SW17 0RE, UK.
authors.forename: Marios C
authors.initials: MC
authors.lastname: Papadopoulos
authors.affiliation: Departments of Neurology and Ophthalmology, University of Colorado School of Medicine, Research Complex 2, Mail stop B-182, 12700 East 19th Avenue, Aurora, CO 80045, USA.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Bennett
authors.affiliation: Department of Medicine, University of California, San Francisco, Health Science East Tower Room 1246, 513 Parnassus Avenue, San Francisco, CA 94143, USA.
authors.forename: Alan S
authors.initials: AS
authors.lastname: Verkman
mesh_terms: D006801:Humans; D009471:Neuromyelitis Optica / Q000175:diagnosis / Q000473:pathology* / Q000628:therapy*
references.citation: Arch Neurol. 2008 Nov;65(11):1443-8
references.pmid: 18779415
references.citation: Adv Exp Med Biol. 2013;735:1-22
references.pmid: 22990692
references.citation: Med Hypotheses. 2009 Sep;73(3):361-2
references.pmid: 19398170
references.citation: Rinsho Shinkeigaku. 2013;53(7):513-7
references.pmid: 23892961
references.citation: Mol Pharmacol. 2013 Jun;83(6):1268-75
references.pmid: 23571414
references.citation: Neurology. 2007 May 8;68(19):1614-7
references.pmid: 17485649
references.citation: Exp Neurol. 2014 May;255:145-53
references.pmid: 24636863
references.citation: N Engl J Med. 2012 Nov 22;367(21):2015-25
references.pmid: 23171098
references.citation: Immunol Res. 1993;12(3):258-75
references.pmid: 7507156
references.citation: Neurology. 2011 Sep 20;77(12):1149-55
references.pmid: 21900637
references.citation: J Neurol Sci. 2011 Jan 15;300(1-2):19-22
references.pmid: 21056429
references.citation: Ann Neurol. 2012 Mar;71(3):323-33
references.pmid: 22374891
references.citation: Nat Rev Immunol. 2009 Oct;9(10):729-40
references.pmid: 19730437
references.citation: Neurology. 2008 Jul 8;71(2):93-100
references.pmid: 18509092
references.citation: J Neurol Neurosurg Psychiatry. 2013 Aug;84(8):918-21
references.pmid: 23467418
references.citation: J Neuroimmunol. 2011 May;234(1-2):155-60
references.pmid: 21489641
references.citation: J Neurochem. 2011 Jan;116(1):53-66
references.pmid: 21044081
references.citation: Mod Rheumatol. 2013 Jul;23(4):827-31
references.pmid: 22782533
references.citation: Mult Scler. 2012 Oct;18(10):1480-3
references.pmid: 22354738
references.citation: Mod Rheumatol. 2016;26(2):294-6
references.pmid: 24313919
references.citation: Int MS J. 2008 Sep;15(3):75-8
references.pmid: 18812056
references.citation: Brain. 2008 Nov;131(Pt 11):3072-80
references.pmid: 18945724
references.citation: Acta Neuropathol. 2012 Jun;123(6):861-72
references.pmid: 22526022
references.citation: Autoimmunity. 2014 May;47(3):154-61
references.pmid: 24512514
references.citation: Neurology. 2010 Nov 9;75(19):1740-4
references.pmid: 21060098
references.citation: J Biol Chem. 2011 Dec 30;286(52):45156-64
references.pmid: 22069320
references.citation: Ann Neurol. 2009 Nov;66(5):617-29
references.pmid: 19938104
references.citation: J Neuroimmunol. 2011 Jun;235(1-2):27-32
references.pmid: 21492943
references.citation: Mult Scler. 2012 Jan;18(1):108-12
references.pmid: 21868485
references.citation: Intern Med. 2007;46(19):1671-2
references.pmid: 17917332
references.citation: Pediatrics. 2008 Nov;122(5):e1039-47
references.pmid: 18838462
references.citation: Mult Scler. 2007 Sep;13(8):968-74
references.pmid: 17623727
references.citation: Arch Neurol. 2010 Sep;67(9):1131-6
references.pmid: 20837859
references.citation: Neurology. 2011 Apr 12;76(15):1310-5
references.pmid: 21482945
references.citation: Acta Neuropathol. 2013 Jun;125(6):829-40
references.pmid: 23677375
references.citation: Acta Neuropathol. 2013 Nov;126(5):699-709
references.pmid: 23995423
references.citation: Nat Med. 2000 Oct;6(10):1167-75
references.pmid: 11017150
references.citation: Mol Immunol. 2009 Sep;46(14):2774-83
references.pmid: 19481265
references.citation: Virulence. 2014 Jan 1;5(1):98-126
references.pmid: 24104403
references.citation: Neurology. 2010 Jul 27;75(4):310-5
references.pmid: 20660861
references.citation: Brain. 2010 Feb;133(Pt 2):349-61
references.pmid: 20047900
references.citation: Eur J Neurol. 2010 Jun 1;17(6):794-9
references.pmid: 20100229
references.citation: J Cell Biol. 2010 Nov 1;191(3):677-91
references.pmid: 20974816
references.citation: Arch Neurol. 2012 Feb;69(2):239-45
references.pmid: 22332191
references.citation: Clin Chim Acta. 2013 Jun 5;421:181-3
references.pmid: 23535508
references.citation: Med Hypotheses. 2013 Dec;81(6):1090-5
references.pmid: 24182872
references.citation: J Biol Chem. 2012 Oct 26;287(44):36837-44
references.pmid: 22989877
references.citation: Neurology. 2010 Oct 19;75(16):1423-7
references.pmid: 20826711
references.citation: Neuroimmunomodulation. 2012;19(5):304-8
references.pmid: 22777162
references.citation: PLoS One. 2013 Dec 10;8(12):e83036
references.pmid: 24340077
references.citation: Acta Neuropathol. 2014 Apr;127(4):523-38
references.pmid: 24292009
references.citation: JAMA Neurol. 2013 Nov;70(11):1375-81
references.pmid: 23999580
references.citation: J Neurol. 2013 Oct;260(10):2614-9
references.pmid: 23835638
references.citation: Brain. 2002 Jul;125(Pt 7):1450-61
references.pmid: 12076996
references.citation: Lancet. 1981 Jun 6;1(8232):1228-31
references.pmid: 6112565
references.citation: Ann Rheum Dis. 2011 Dec;70(12):2071-4
references.pmid: 21873334
references.citation: Mult Scler. 2011 Oct;17(10):1225-30
references.pmid: 21622594
references.citation: Tissue Antigens. 2009 Feb;73(2):171-6
references.pmid: 19140826
references.citation: Lancet Neurol. 2013 Jun;12(6):554-62
references.pmid: 23623397
references.citation: Immunol Rev. 2011 Jul;242(1):161-77
references.pmid: 21682744
references.citation: J Neuroimmunol. 2011 Jul;236(1-2):81-6
references.pmid: 21621856
references.citation: EMBO J. 2001 Jun 15;20(12):3046-55
references.pmid: 11406581
references.citation: Acta Neuropathol Commun. 2014 Mar 31;2:35
references.pmid: 24685353
references.citation: Arch Neurol. 2010 Aug;67(8):1016-7
references.pmid: 20697055
references.citation: Mult Scler. 2013 Jul;19(8):1052-9
references.pmid: 23257621
references.citation: Neurology. 2007 Feb 20;68(8):603-5
references.pmid: 17310032
references.citation: J Neurol. 2009 Jan;256(1):35-44
references.pmid: 19224310
references.citation: Mult Scler. 2009 Feb;15(2):229-37
references.pmid: 18805841
references.citation: J Neurosci. 2004 Mar 3;24(9):2143-55
references.pmid: 14999065
references.citation: Am J Pathol. 2010 Oct;177(4):1881-7
references.pmid: 20802177
references.citation: J Clin Invest. 2013 May;123(5):2306-16
references.pmid: 23563310
references.citation: J Exp Med. 2008 Oct 27;205(11):2473-81
references.pmid: 18838545
references.citation: J Child Neurol. 2007 Sep;22(9):1143-6
references.pmid: 17890418
references.citation: J Neuroinflammation. 2014 Jan 27;11:16
references.pmid: 24468108
references.citation: J Neurol Neurosurg Psychiatry. 2012 Mar;83(3):288-97
references.pmid: 22100760
references.citation: Mult Scler. 2012 Jan;18(1):113-5
references.pmid: 22146605
references.citation: Neurology. 2002 Jan 8;58(1):143-6
references.pmid: 11781423
references.citation: Arch Neurol. 2007 Oct;64(10):1407-15
references.pmid: 17698695
references.citation: JAMA Neurol. 2013 Sep 1;70(9):1110-7
references.pmid: 23897062
references.citation: N Engl J Med. 2006 Mar 2;354(9):899-910
references.pmid: 16510744
references.citation: Brain. 2007 May;130(Pt 5):1206-23
references.pmid: 17439988
references.citation: JAMA Neurol. 2014 Mar;71(3):276-83
references.pmid: 24425068
references.citation: FASEB J. 2012 May;26(5):2197-208
references.pmid: 22319008
references.citation: Nat Clin Pract Neurol. 2008 Apr;4(4):202-14
references.pmid: 18334978
references.citation: Int J Dev Neurosci. 2006 Aug;24(5):295-305
references.pmid: 16814974
references.citation: Mult Scler. 2012 Dec;18(12):1801-3
references.pmid: 22495946
references.citation: J Neurol Neurosurg Psychiatry. 2006 Sep;77(9):1073-5
references.pmid: 16505005
references.citation: Can J Neurol Sci. 2004 May;31(2):265-7
references.pmid: 15198456
references.citation: Intern Med. 2010;49(22):2423-32
references.pmid: 21088343
references.citation: Nat Rev Neurol. 2013 Aug;9(8):455-61
references.pmid: 23797245
references.citation: Neurology. 2012 Mar 20;78(12):875-9
references.pmid: 22402855
references.citation: Neurologia. 2013 Mar;28(2):65-72
references.pmid: 22841880
references.citation: Brain. 2012 Jun;135(Pt 6):1834-49
references.pmid: 22577216
references.citation: Clin Rev Allergy Immunol. 2013 Apr;44(2):114-20
references.pmid: 22231516
references.citation: Ann Neurol. 2013 Jan;73(1):77-85
references.pmid: 23055279
references.citation: MAbs. 2012 Sep-Oct;4(5):571-7
references.pmid: 22820352
references.citation: Lancet. 2004 Dec 11-17;364(9451):2106-12
references.pmid: 15589308
references.citation: Arch Neurol. 2009 Sep;66(9):1128-33
references.pmid: 19752302
references.citation: Mult Scler. 2014 Apr;20(4):501-4
references.pmid: 23986097
references.citation: Arch Neurol. 2011 Nov;68(11):1412-20
references.pmid: 21747007
references.citation: Mult Scler. 2009 Apr;15(4):487-92
references.pmid: 19324982
references.citation: Glia. 2012 Dec;60(12):2027-39
references.pmid: 22987455
references.citation: JAMA Neurol. 2013 Mar 1;70(3):394-7
references.pmid: 23358868
references.citation: J Neurol Sci. 2007 Jan 15;252(1):57-61
references.pmid: 17125797
references.citation: BMJ. 2009 Dec 10;339:b4026
references.pmid: 20007656
references.citation: J Neuroinflammation. 2011 Dec 28;8:184
references.pmid: 22204662
references.citation: Lancet Neurol. 2012 Jun;11(6):535-44
references.pmid: 22608667
references.citation: J Biol Chem. 2012 Apr 20;287(17):13829-39
references.pmid: 22393049
references.citation: Intern Med. 2013;52(9):969-72
references.pmid: 23648715
references.citation: Mult Scler. 2011 Jan;17(1):24-31
references.pmid: 20861181
references.citation: Neurology. 2012 Sep 18;79(12):1273-7
references.pmid: 22914827
references.citation: Mult Scler Relat Disord. 2012 Oct;1(4):180-187
references.pmid: 24555176
references.citation: J Neurol Neurosurg Psychiatry. 2011 Dec;82(12):1360-4
references.pmid: 21665917
references.citation: Lancet Oncol. 2009 Aug;10(8):816-24
references.pmid: 19647202
references.citation: Acta Neuropathol Commun. 2013 Dec 24;1:85
references.pmid: 24367907
references.citation: J Neurol. 2014 Jan;261(1):1-16
references.pmid: 24272588
references.citation: J Neurol Sci. 2014 Apr 15;339(1-2):223-5
references.pmid: 24576801
references.citation: Arch Neurol. 2006 Jul;63(7):957-63
references.pmid: 16831964
references.citation: J Immunol. 2008 Oct 15;181(8):5730-7
references.pmid: 18832732
references.citation: Cold Spring Harb Perspect Biol. 2012 Nov 01;4(11):
references.pmid: 23125012
references.citation: J Neurosci. 2009 Sep 16;29(37):11511-22
references.pmid: 19759299
references.citation: J Inflamm (Lond). 2009 Jun 02;6:18
references.pmid: 19490629
references.citation: In Vivo. 2007 Sep-Oct;21(5):813-7
references.pmid: 18019416
references.citation: Ther Apher Dial. 2009 Dec;13(6):505-8
references.pmid: 19954473
references.citation: Nat Immunol. 2011 Feb;12(2):151-9
references.pmid: 21217761
references.citation: Neurology. 2006 May 23;66(10):1485-9
references.pmid: 16717206
references.citation: Chem Biol. 2013 Mar 21;20(3):351-9
references.pmid: 23521793
references.citation: Eur J Pharmacol. 2006 Mar 8;533(1-3):2-14
references.pmid: 16436275
references.citation: Autoimmun Rev. 2013 Apr;12(6):657-60
references.pmid: 23201918
references.citation: Mult Scler Int. 2012;2012:787630
references.pmid: 22474589
references.citation: Br J Haematol. 2014 Feb;164(3):342-51
references.pmid: 24172059
references.citation: J Immunol. 2013 Sep 15;191(6):2999-3005
references.pmid: 23935196
references.citation: Arch Neurol. 2011 Apr;68(4):473-9
references.pmid: 21149806
references.citation: Neurology. 2011 May 3;76(18):1589-95
references.pmid: 21536639
references.citation: J Biol Chem. 2011 May 6;286(18):16516-24
references.pmid: 21454592
references.citation: Neuroreport. 2012 Dec 19;23(18):1044-7
references.pmid: 23108041
references.citation: Ann Neurol. 2011 Dec;70(6):943-54
references.pmid: 22069219
references.citation: Neurology. 2007 Dec 11;69(24):2221-31
references.pmid: 17928579
references.citation: JAMA Neurol. 2014 Mar;71(3):324-30
references.pmid: 24445513
references.citation: J Exp Med. 2005 Aug 15;202(4):473-7
references.pmid: 16087714
references.citation: Nat Rev Neurol. 2010 Jul;6(7):383-92
references.pmid: 20639914
references.citation: Neurology. 2014 Feb 11;82(6):466-7
references.pmid: 24415570
references.citation: Neurology. 2001 Feb 27;56(4):507-14
references.pmid: 11222796
references.citation: J Neuroimmunol. 2012 Feb 29;243(1-2):73-80
references.pmid: 22245284
references.citation: Mult Scler. 2009 Aug;15(8):1006-8
references.pmid: 19667025
references.citation: Neurology. 2011 Aug 16;77(7):659-66
references.pmid: 21813788
references.citation: J Neuroinflammation. 2012 Jan 19;9:14
references.pmid: 22260418
references.citation: JAMA Neurol. 2013 Mar 1;70(3):390-3
references.pmid: 23599943
references.citation: Neurology. 2008 Jan 29;70(5):344-52
references.pmid: 18094334
references.citation: Arch Ophthalmol. 2012 Jul;130(7):858-62
references.pmid: 22776923
references.citation: Proc Natl Acad Sci U S A. 2011 Mar 1;108(9):3701-6
references.pmid: 21321193
references.citation: Arch Neurol. 2010 Oct;67(10):1201-8
references.pmid: 20937947
references.citation: Clin Dev Immunol. 2006 Jun-Dec;13(2-4):143-57
references.pmid: 17162357
references.citation: Curr Neuropharmacol. 2009 Dec;7(4):337-42
references.pmid: 20514213
references.citation: J Neurol Sci. 2011 Jul 15;306(1-2):82-90
references.pmid: 21550068
references.citation: Mult Scler. 2009 May;15(5):571-9
references.pmid: 19299434
references.citation: Ann Neurol. 2012 Jul;72(1):53-64
references.pmid: 22807325
references.citation: Placenta. 2011 Mar;32 Suppl 2:S207-11
references.pmid: 21208655
references.citation: J Clin Neurosci. 2011 Oct;18(10):1313-7
references.pmid: 21795048
references.citation: Nat Rev Rheumatol. 2009 Oct;5(10):572-7
references.pmid: 19798033
references.citation: J Immunol. 2004 Apr 1;172(7):4493-502
references.pmid: 15034066
references.citation: Neurology. 2005 Apr 12;64(7):1270-2
references.pmid: 15824362
references.citation: Eur J Neurosci. 1999 Mar;11(3):935-45
references.pmid: 10103087
references.citation: Neurology. 2012 Apr 17;78(16):1264-7
references.pmid: 22491862
references.citation: J Autoimmun. 2014 Sep;53:67-77
references.pmid: 24698947
references.citation: J Neurol Neurosurg Psychiatry. 2008 Sep;79(9):1022-6
references.pmid: 18356258
references.citation: Neurology. 2014 Feb 11;82(6):474-81
references.pmid: 24415568
references.citation: Biochem Biophys Res Commun. 1991 Jun 14;177(2):814-20
references.pmid: 2049103
references.citation: Arch Neurol. 2012 Jul;69(7):938-9
references.pmid: 22777264
references.citation: J Neurol Neurosurg Psychiatry. 2013 Aug;84(8):922-30
references.pmid: 23142960
references.citation: Nat Biotechnol. 2007 Nov;25(11):1265-75
references.pmid: 17989689
references.citation: Mult Scler. 2010 Jan;16(1):21-9
references.pmid: 19995845
references.citation: Acta Neuropathol. 2014 Apr;127(4):539-51
references.pmid: 24190619
references.citation: J Neuroinflammation. 2010 Sep 08;7:52
references.pmid: 20825655
references.citation: Mult Scler. 2012 Jul;18(7):1022-6
references.pmid: 22261118
references.citation: J Clin Immunol. 2013 Jan;33(1):179-89
references.pmid: 22948743
references.citation: Proc Natl Acad Sci U S A. 2012 Jan 24;109(4):1245-50
references.pmid: 22128336
references.citation: Ann Neurol. 2012 Mar;71(3):314-22
references.pmid: 22271321
references.citation: Mult Scler. 2013 Oct;19(11):1544-7
references.pmid: 23886825
references.citation: J Child Neurol. 2012 Nov;27(11):1437-47
references.pmid: 22859697
references.citation: J Neurol. 2013 Feb;260(2):627-34
references.pmid: 23076828