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  • Review Article
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Treatment of neuromyelitis optica: state-of-the-art and emerging therapies

Nature Reviews Neurology volume 10, pages 493–506 (2014)Cite this article

Subjects

Key Points

  • Most patients with neuromyelitis optica (NMO) have serum IgG antibodies against astrocytic aquaporin-4 (AQP4) channels, a minority have antibodies to myelin oligodendrocyte glycoprotein, and some have neither

  • Current NMO treatments include corticosteroids and plasma exchange, which reduce the severity of acute attacks, and prednisolone, rituximab, cyclophosphamide, azathioprine, mycophenolate, mitoxantrone, methotrexate and cyclosporine, which prevent relapses

  • Some multiple sclerosis treatments, such as IFN-β, fingolimod and natalizumab, can be harmful in NMO

  • Approved therapies with potential for repurposing in NMO include eculizumab (complement inhibitor), tocilizumab (IL-6 receptor inhibitor), sivelestat and cetirizine (granulocyte inhibitors), intravenous immunoglobulin, CD19-depleting agents, and anti-TNF therapy

  • Potential therapeutic approaches include inhibition of AQP4-IgG binding (aquaporumab, small molecules), AQP4-IgG inactivation (endoglycosidase S, IgG-degrading enzyme), alternative complement inhibitors (C1inh, compstatin, CD59), anti-FcγRIII antibody, VEGF inhibition (bevacizumab), and antigen-specific tolerization

  • Challenges for NMO therapeutics include optimization of drug penetration into NMO lesions, clinical trial design (given the small patient numbers), and management of seronegative patients

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.

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Figure 1: Mechanisms of NMO pathogenesis.
Figure 2: Pharmacological targets in NMO.
Figure 3: AQP4-IgG blocking and inactivation strategies for NMO therapy.
Figure 4: Complement activation pathways and complement drug targets.

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Acknowledgements

M.C.P., J.L.B. and A.S.V. have received funding from the Guthy-Jackson Charitable Foundation, and J.L.B. and A.S.V. have received funding from the NIH.

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Authors and Affiliations

  1. Academic Neurosurgery Unit, St George's, University of London, Room 0.136 Jenner Wing, Cranmer Terrace, London, SW17 0RE, Tooting, UK

    Marios C. Papadopoulos

  2. Departments of Neurology and Ophthalmology, University of Colorado School of Medicine, Research Complex 2, Mail stop B-182, 12700 East 19th Avenue, Aurora, 80045, CO, USA

    Jeffrey L. Bennett

  3. Department of Medicine, University of California, San Francisco, Health Science East Tower Room 1246, 513 Parnassus Avenue, San Francisco, 94143, CA, USA

    Alan S. Verkman

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All three authors researched the data for the article, provided substantial contributions to discussions of the content, and wrote the article.

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Correspondence to Marios C. Papadopoulos.

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Competing interests

M.C.P. has received consulting income from ONO Pharmaceutical. J.L.B. has received consulting income from MedImmune and Chugai Pharmaceuticals. He has a patent application on aquaporumab technology and is a member of the board of directors of Apsara Therapeutics. A.S.V. has patent applications on aquaporumab and EndoS technology and is a member of the board of directors of Apsara Therapeutics.

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Papadopoulos, M., Bennett, J. & Verkman, A. Treatment of neuromyelitis optica: state-of-the-art and emerging therapies. Nat Rev Neurol 10, 493–506 (2014). https://doi.org/10.1038/nrneurol.2014.141

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