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.

Figure 1

Mechanisms of NMO pathogenesis. Serum AQP4-IgG and plasma cells that produce AQP4-IgG penetrate the CNS, resulting in binding of AQP4-IgG to AQP4 channels on astrocytes. Antibody-dependent astrocyte damage involving complement-dependent cytotoxicity, CDCC and ADCC mechanisms lead to inflammation, oligodendrocyte injury, demyelination and neuronal loss. The CD59 glycoprotein inhibits cell lysis by inhibiting formation of the MAC. Abbreviations: ADCC, antibody-dependent cellular cytotoxicity; AQP4, aquaporin-4; CDC, complement-dependent cytotoxicity; CDCC, complement-dependent cellular cytotoxicity; MAC, membrane attack complex; NMO, neuromyelitis optica.

Figure 2

Pharmacological targets in NMO. Green boxes show mechanism-based approches currently used to treat NMO (anti-CD20 antibody [rituximab]; immunosuppressive agents; plasma exchange), purple boxes show approved drugs under evaluation for repurposing for NMO, blue boxes show drugs in preclinical development, and orange boxes show pharmacological intervention strategies at early, proof-of-concept stage. See Table 1 for additional information. Abbreviations: ADCC, antibody-dependent cellular cytotoxicity; AQP4, aquaporin-4; CDC, complement-dependent cytotoxicity; IVIg, intravenous immunoglobulin; NMO, neuromyelitis optica.

Figure 3

AQP4-IgG blocking and inactivation strategies for NMO therapy. An AQP4 array with bound AQP4-IgG antibody is shown in the middle of the figure. High-affinity, nonpathogenic anti-AQP4 antibody (aquaporumab) competes with pathogenic AQP4-IgG for AQP4 binding. Streptococcus pyogenes-derived enzymes IdeS and EndoS selectively inactivate IgG through proteinase and endoglycosidase actions, respectively, producing blocking nonpathogenic antibody remnants. Abbreviations: ADCC, antibody-dependent cellular cytotoxicity; AQP4, aquaporin-4; C1q, complement component C1q; CDC, complement-dependent cytotoxicity; CDCC, complement-dependent cellular cytotoxicity; CL, constant region of light chain; EndoS, endoglycosidase S; Fab, fragment antigen-binding region; Fuc, fucose; Gal, galactose; GlcNAc, N-acetylglucosamine; IdeS, IgG-degrading enzyme; Man, mannose; NMO, neuromyelitis optica; Sial, sialic acid; VH, variable region of heavy chain; VL, variable region of light chain.

Figure 4

Complement activation pathways and complement drug targets. The major components of the classical, alternative and lectin complement activation pathways are shown, along with C1mAb and eculizumab—monoclonal antibodies that target complement components C1 and C5, respectively; C1inh, which targets C1; and the cyclic oligopeptide compstatin, which targets C5. C3a and C5a anaphylatoxins cause granulocyte activation by binding to specific receptors. Abbreviations: AQP4, aquaporin-4; C1inh, complement protein 1 inhibitor; MAC, membrane attack complex; MASP, mannan-binding lectin serine protease; MBL, mannose-binding protein.