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. Author manuscript; available in PMC: 2021 Mar 9.
Published in final edited form as: Expert Opin Ther Targets. 2020 Mar 2;24(3):219–229. doi: 10.1080/14728222.2020.1732927

Emerging therapeutic targets for neuromyelitis optica spectrum disorders

Lukmanee Tradtrantip 1, Nithi Asavapanumas 2, Alan S Verkman 1
PMCID: PMC7941255  NIHMSID: NIHMS1567497  PMID: 32070155

Abstract

Introduction:

Neuromyelitis optica spectrum disorders (NMOSD) are inflammatory demyelinating diseases of the central nervous system affecting primarily the spinal cord and optic nerve. Most NMOSD patients are seropositive for immunoglobulin G autoantibodies against astrocyte water channel aquaporin-4, called AQP4-IgG, which cause astrocyte injury leading to demyelination and neurological impairment. Current therapy for AQP4-IgG seropositive NMOSD includes immunosuppression, B cell depletion and plasma exchange. Newer therapies target complement, CD19 and IL-6 receptors.

Areas covered:

This review covers early-stage pre-clinical therapeutic approaches for seropositive NMOSD. Targets include pathogenic AQP4-IgG autoantibodies and their binding to AQP4, complement-dependent and cell-mediated cytotoxicity, blood-brain barrier, remyelination and immune effector and regulatory cells, with treatment modalities including small molecules, biologics and cells.

Expert opinion:

Though newer NMOSD therapies appear to have increased efficacy in reducing relapse rate and neurological deficit, increasingly targeted therapies could benefit NMOSD patients with ongoing relapses and could potentially be superior in efficacy and safety. Of the various early-stage therapeutic approaches, IgG inactivating enzymes, aquaporumab blocking antibodies, drugs targeting early components of the classical complement system, complement regulator-targeted drugs, and Fc-based multimers are of interest. Curative strategies, perhaps involving AQP4 tolerization, remain intriguing future possibilities.

Keywords: NMOSD, autoimmunity, aquaporin-4, astrocyte, complement, neuroinflammation

1. Introduction

Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory demyelinating disease of the central nervous system that generally affect spinal cord and optic nerve to a greater extent than brain. The majority of NMOSD patients are seropositive for immunoglobulin G autoantibodies against aquaporin-4 (called AQP4-IgG), a water channel expressed at the plasma membrane of astrocytes throughout the central nervous system (CNS), as well as in skeletal muscle and some epithelial cell types. A central initiating event in the pathogenesis of AQP4-IgG seropositive NMOSD is AQP4-IgG binding to astrocyte AQP4, which causes astrocyte injury by complement and cellular mechanisms, resulting in an inflammatory response, blood-brain barrier disruption, and oligodendrocyte and neuronal injury.

Current NMOSD therapy includes immunosuppression using a wide variety of drugs, B cell depletion by targeting CD20 with rituximab, and plasma exchange [1,2]. Eculizumab, which binds to complement component C5 and prevents its cleavage by C5 convertase, was recently approved to treat seropositive NMOSD [3]. Recent clinical trials have also shown significant benefit of satralizumab [4], an interleukin-6 receptor inhibitor, and inebilizumab [5], which targets CD19-expressing B cells, plasma cells and plasmablasts. While conventional NMOSD therapies, particularly rituximab [6], are generally effective in preventing NMOSD relapses, and newer therapies may be more effective, a subset of NMOSD patients suffer disease relapses and progressive neurological impairment despite aggressive therapy, and some patients develop serious side effects including infection and neoplasm. There thus remains continued interest in developing effective and safe therapies to treat NMOSD disease exacerbations and prevent relapses.

This review is focused on early-stage, pre-clinical targets and potential therapeutics for AQP4-IgG seropositive NMOSD with mechanisms of action that are largely distinct from those of the aforementioned drugs.

2. Pathogenesis mechanisms of AQP4-IgG seropositive NMOSD

Current understanding of disease pathogenesis mechanisms is reviewed briefly as it relates to therapeutic targets and strategies. The reader is referred to recent reviews for details of the evidence supporting the pathogenesis mechanisms [7–10], and on the biology of AQP4 [11], the target of AQP4-IgG autoantibody. Figure 1 summarizes the major features of disease pathogenesis of seropositive NMOSD as currently understood, as well as current and potential therapies and targets.

Figure 1. Pathogenesis mechanism of AQP4-IgG seropositive NMOSD and therapeutic targets.

Figure 1.

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Pathogenesis of AQP4-IgG seropositive NMOSD involves generation of AQP4-IgG autoantibody in the periphery and its entry into the CNS. AQP4-IgG binding to astrocyte AQP4 initiates CDC and ADCC mechanisms, which results in astrocyte injury and an inflammatory response leading to oligodendrocyte injury, demyelination and neuron injury. Conventional, new and potential future therapies and targets are indicated. See text for further explanations. ADCC, antibody-dependent cellular cytotoxicity; AQP4, aquaporin-4; AQP4-IgG, aquaporin-4-immunoglobulin G; IL6R, CDC, complement-dependent cytotoxicity; CNS, central nervous system; interleukin-6 receptor.

The target of the AQP4-IgG autoantibody, AQP4, is a plasma membrane protein that transports water in response to an osmotic gradient. AQP4 is expressed in astrocytes throughout the CNS, including spinal cord, optic nerve and brain, as well as in skeletal muscle and various epithelial cells in kidney, stomach, airways and exocrine glands. Of relevance to disease pathogenesis of seropositive NMOSD, plasma membrane AQP4 assembles in large supramolecular aggregates called orthogonal arrays of particles (OAPs), which in general increases the binding affinity of AQP4-IgG autoantibodies [12].

AQP4-IgG, which is produced by plasma cells primarily outside of the CNS, may under certain conditions move across the blood-brain barrier (BBB) and bind to astrocyte AQP4. The origin of the AQP4-IgG-producing plasma cells may involve inappropriate recognition of AQP4 by T cells leading to expansion of B cell populations that differentiate into plasmablasts [7]. As AQP4-IgG is an IgG1-class antibody, its Fc region contains complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) effector functions that can cause primary astrocyte injury. CDC involves activation of the classical complement pathway initiated by multivalent binding of complement protein C1q to AQP4-bound AQP4-IgG [13]. Complement activation results in generation of anaphylotoxins C3a and C5a, which function as leukocyte chemotaxic factor, as well as the terminal membrane attack complex (MAC, or C5b-9), which causes cell lysis. Complement activation is modulated by complement regulator proteins that inhibit MAC formation, such as membrane-associated CD59. ADCC involves binding of leukocytes to the Fc region of AQP4-IgG through Fc receptors, resulting in their activation and degranulation. The inflammatory environment created by astrocyte injury, microglial activation, and infiltration of neutrophils, eosinophils and macrophages, can promote BBB disruption and oligodendrocyte injury, resulting in myelin loss and neuronal injury.

How AQP4-IgG causes injury to cells that do not express AQP4, such as oligodendrocytes and neurons, is an important issue. Secondary injury to ‘bystander’ cells that do not express AQP4 may occur from the inflammatory environment with release of soluble immune mediators such as cytokines from injured astrocytes and leukocytes. In addition, more direct mechanisms may account for the early and marked myelin loss and neuronal injury in seropositive NMOSD, such as complement- and ADCC-dependent bystander injury [14–16], as discussed further below. Other proposed though unsubstantiated mechanisms include release of excitotoxic compounds such as glutamate from injured astrocytes and AQP4-IgG inhibition of AQP4 water permeability [17,18]. Questions also remain on how AQP4-IgG enters the CNS to initiate disease. Proposed mechanisms include non-specific inflammation, infiltration of CNS-specific T cells, and direct AQP4-IgG penetration through small parenchymal vessels [19]. As discussed further below with regard to the BBB as a therapeutic target, NMOSD patient sera may, in addition to AQP4-IgG, sometimes contain antibodies that target and injure microvascular endothelial cells [20]. Data from experimental animal models of seropositive NMOSD are beginning to inform on these possibilities (reviewed in refs. [9,21]). How AQP4 self-tolerance is lost in NMOSD also remains unknown, with some data suggesting molecular mimicry, potentially to an ATP binding cassette permease expressed in Clostridium perfringens [22].

3. AQP4-IgG and its binding to AQP4

3.1. AQP4-IgG inactivation or depletion

As AQP4-IgG has a central role in the pathogenesis of seropositive NMOSD, its inactivation or depletion could provide therapeutic benefit. The beneficial action of plasma exchange in NMOSD may be due in part to AQP4-IgG depletion. One approach to accomplish AQP4-IgG inactivation uses bacterial enzymes that selectively target IgG-class antibodies. Endoglycosidase S (EndoS) from Streptococcus pyogenes digests asparagine-linked glycans on IgG heavy chains, with the resultant deglycosylated antibody deficient in cytotoxicity effector functions [23]. EndoS treatment of NMO patient serum prevented CDC and ADCC in vitro, and pathology in an experimental animal model of seropositive NMOSD [24]. In addition to neutralization of antibody effector functions, the EndoS-treated, deglycosylated antibody competitively inhibits binding of pathogenic AQP4-IgG to AQP4, thus converting pathogenic AQP4-IgG into a therapeutic blocking antibody. Another bacterial enzyme, IdeS (IgG-degrading enzyme of Streptococcus pyogenes), selectively cleaves IgG antibodies to yield Fc and F(ab’)2 fragments, which are non-pathogenic and also inhibit AQP4-IgG binding to AQP4 [25]. EndoS or IdeS treatment of blood by therapeutic apheresis using surface-immobilized enzyme or by direct intravenous enzyme administration may thus be beneficial in seropositive NMOSD both for prevention and treatment of disease exacerbations. These enzymes have shown efficacy in animal models of at least eight other antibody-driven autoimmune disorders [26]; clinical trials are in progress testing IdeS (imlifidase) in kidney transplantation [27].

An interesting approach to accomplish IgG depletion of theoretical utility involves targeting the neonatal Fc receptor (FcRn), which protects IgG from lysosomal degradation [28]. Administration of rozanolixizumab, a FcRn inhibitor, has shown safety in human subjects with reduction in IgG concentration [29]; other FcRn-targeted therapeutics include efgartigimod, M281 and SYNT001. Finally, selective removal of circulating AQP4-IgG by AQP4 immunoadsorption is an attractive but at present theoretical possibility, as it would require engineering of a suitable AQP4-IgG affinity resin. There are several reports of non-selective immunoadsorption therapy in NMOSD using tryptophan or phenylalanine-linked polyvinyl alcohol absorbers, in general reporting similar benefit to plasma exchange [30–33].

3.2. Prevention of AQP4-IgG binding to AQP4

As binding of pathogenic AQP4-IgG to AQP4 on the astrocyte plasma membrane is a primary initiating event in pathogenesis of seropositive NMOSD, pharmacological blockade of AQP4-IgG binding to AQP4, using a small molecule or targeted biologic, is a logical therapeutic strategy. Screening of approved and investigational small-molecule drugs and nutraceuticals identified several blockers of AQP4-IgG binding to AQP4 that showed efficacy in experimental animal models of seropositive NMOSD [34], albeit with limited potency and CNS penetration. Subsequently, a biologic approach was developed using an engineered, high-affinity monoclonal anti-AQP4 antibody [35]. The blocking antibody, called ‘aquaporumab’, was generated from rAb-53, a high-affinity human monoclonal AQP4-IgG identified by sequence analysis of plasma cells from cerebrospinal fluid of a seropositive NMOSD patient [36]. Fc mutations L234A/L235A were introduced in the antibody Fc region to neutralize its CDC and ADCC effector functions, and additional mutations identified by affinity maturation [37] were introduced into the Fab sequence to increase antibody binding affinity to AQP4 (Figure 2A). Because of the relatively large size of the IgG1-class aquaporumab antibody compared to AQP4, a sufficiently high concentration of aquaporumab is predicted to sterically block binding of the relatively low-affinity polyclonal AQP4-IgG in patient serum. Aquaporumab binding to AQP4 measured in cell cultures showed a binding affinity of ~18 ng/ml (~120 pM, Figure 2B), and increasing concentrations of aquaporumab prevented CDC produced by seropositive NMOSD patient sera with IC50 ranging from 40–80 ng/ml (Figure 2C). Aquaporumab efficacy was also demonstrated in rodent and spinal cord slice models of seropositive NMOSD [35].

Figure 2. Aquaporumab antibody block of AQP4-IgG binding to AQP4.

Figure 2.

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A. Diagram of aquaporumab, an engineered monoclonal antibody with high affinity for binding to AQP4 that contains Fc mutations that neutralize its complement and cellular cytotoxicity effector functions. Aquaporumab shown on the same scale as membrane AQP4. B. Aquaporumab binding to AQP4 in cell cultures measured using a cell-based ELISA. C. Aquaporumab protection against complement-dependent cytotoxicity in AQP4-expressing cells exposed to sera from AQP4-IgG seropositive NMOSD patient together with human complement. Adapted from ref. [37]. Duan T, Tradtrantip L, Phuan PW, et al. Affinity-matured ‘aquaporumab’ anti-aquaporin-4 antibody for therapy of seropositive neuromyelitis optica spectrum disorders. Neuropharmacology. 2020 Jan 1;162:107827. AQP4-IgG, aquaporin-4-immunoglobulin G.

Aquaporumab offers a highly targeted, non-immunosuppressive approach for therapy of AQP4-IgG seropositive NMOSD. If safe and effective, aquaporumab may be suitable as monotherapy, both to treat and prevent disease exacerbations, or in combination with currently used drugs such as immunosuppressants. The safety of aquaporumab in humans awaits clinical testing, though the observation that NMOSD patients can be seropositive for many years prior to clinical disease manifestations suggests minimal toxicity of an anti-AQP4 antibody lacking cytotoxicity effector functions. The efficacy of aquaporumab in humans must await clinical trials as well, as it is difficult to extrapolate from in vitro and animal studies the AQP4 affinity and CNS penetration needed for effective blocking of AQP4-IgG autoantibody binding to AQP4 on astrocytes.

4. Complement

4.1. Complement inhibition

Complement plays a central role in the pathogenesis of seropositive NMOSD, as evidenced by vasculocentric deposition of activated complement in human NMOSD tissues, complement-dependent pathology in rodent models of seropositive NMOSD produced by passive transfer of AQP4-IgG, and eculizumab clinical trials data [7,8]. Further evidence includes marked NMOSD pathology in rodents lacking complement regulator protein CD59 following AQP4-IgG administration [38,39]. As diagrammed in Figure 3A, AQP4-IgG binding to astrocyte AQP4 activates the classical complement pathway by C1q binding to the Fc portion of AQP4-IgG, which causes direct astrocyte injury by formation of the terminal membrane attack complex (MAC), as well as indirect injury by generation of anaphylotoxins C3a and C5a. In addition to direct astrocyte injury, complement activation by astrocytes results in injury to nearby bystander cells, including oligodendrocytes and neurons, by a mechanism involving the local diffusion of the short-lived, soluble C5b67 complex, leading to MAC formation on bystander cells (Figure 3B) [14,15]. Bystander injury may also occur by an ADCC mechanism in which leukocytes activated by AQP4-IgG on astrocytes injury nearby cells by targeted exocytosis of toxic granule contents [16].

Figure 3. Mechanisms of complement-driven injury in AQP4-IgG seropositive NMOSD.

Figure 3.

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A. Schematic showing astrocyte target, leukocyte and bacterium, with major component of the complement pathway indicated. Activation of the classical complement pathway involves C1q binding to the Fc portion of AQP4-IgG when bound to AQP4 on astrocytes. Major effectors of injury and inflammation include the terminal membrane attack complex (MAC) and anaphylotoxins C3a and C5a. B. Complement bystander injury in which complement activation on astrocytes results in local diffusion of a short-lived, activated complement complex leading to MAC formation on bystander cells. Adapted from ref. [14]. Tradtrantip L, Yao X, Su T, et al. Bystander mechanism for complement-initiated early oligodendrocyte injury in neuromyelitis optica. Acta Neuropathol. 2017 Jul;134(1):35–44.

See text for further explanations. AQP4, aquaporin-4; AQP4-IgG, aquaporin-4-immunoglobulin G; interleukin-6 receptor; MAC, membrane attack complex: MASPs, mannose-binding lectin-associated serine proteases; MBL maltose binding lectin.

The biologic eculizumab, which has been used to treat paroxysmal nocturnal hemoglobinuria (PNH) and hemolytic-uremic syndrome, recently received FDA and EMA approval for treatment of seropositive NMOSD [3]. By inhibition of C5 convertase, eculizumab prevents formation of MAC, which is beneficial in NMOSD but is responsible for its infectious side effects. Also, inhibition of C5 convertase does not interfere with formation of anaphalotoxin C3a. Many new complement-targeted drugs are in clinical development, as motivated by the broad involvement of complement in human diseases and the limitations of eculizumab, which include its high cost, non-optimal pharmacokinetics and consequent challenging dosing schedule, and limited efficacy in PNH. Drugs are in clinical trials that target different components of the complement pathway, including C1r/s, C1s, C3, C5, FD, FB and properdin, and complement receptor C5aR1, and acting by different mechanisms (reviewed in ref. [40]); drugs targeting C2, C5a and C6 are in pre-clinical development. For complement-targeted therapy of NMO, inhibition of early component(s) in the classical complement pathway is theoretically desirable, as it would inhibit formation of C3a, C5a and MAC in the classical pathway without inhibition of bacterial killing by the lectin pathway. Work from our lab showed efficacy of a C1q-targeted neutralizing antibody in in vitro and in vivo models of AQP4-IgG seropositive NMOSD [41]. Many potential complement inhibitors drugs are thus in the development pipeline, which when approved may be suitable for repurposing for treatment and prevention of exacerbations in seropositive NMOSD.

4.2. Upregulate or activate complement regulator proteins

Complement regulator proteins modulate the activation and actions of complement, and hence their upregulation could provide an alternative or adjunctive therapy for seropositive NMOSD that does not interfere directly with the classical, alternative or lectin complement activation pathways. The membrane-associated glycoproteins CD55 (DAC, decay accelerating factor) and CD59 are the major complement regulators on astrocytes; CD55 inhibits complement activation at the early C3/C4 stage, while CD59 inhibits MAC formation. A screen of approved and investigational drugs in a human astrocyte cell line with CD55 and CD59 expression as read-out identified several statins, including the widely used drugs atorvastatin and simvastatin, that increased CD55 expression by a mechanism involving inhibition of the geranylgeranyl transferase pathway [42]. Increased CD55 expression with atorvastatin was seen in primary cultures of murine astrocytes, with consequent inhibition of CDC produced by AQP4-IgG and complement. Orally administered atorvastatin to mice at human-compatible dosing increased CD55 expression in brain and spinal cord, and reduced NMOSD pathology following intracerebral AQP4-IgG injection. CD55 upregulation adds to the list of anti-inflammatory and immunomodulatory actions of atorvastatin that are of potential therapeutic benefit in seropositive NMOSD. As inexpensive, widely used drugs with an established safety record, statins may merit testing in human NMO.

4.3. Multimeric antibody Fc fragments – super-IVIG

Intravenously delivered human immunoglobulin G (IVIG) may have benefit in NMO, though data are largely anecdotal and inconclusive [43,44]. IVIG is reported to have various anti-inflammatory actions including complement inhibition, accelerated autoantibody clearance, cytokine neutralization, blocking of antibody-antigen and antibody-Fc receptor binding, inhibition of leukocyte migration, and others [45]. Animal models of seropositive NMOSD report modest benefit of IVIG [46, 47].

Motivated by the anti-inflammatory properties of the Fc region of human IgG in IVIG, various Fc multimeric therapeutics are in clinical development that target the Fc and neonatal Fc receptors [48–50], with demonstrated efficacy in experimental animal models of arthritis, idiopathic thrombocytopenic purpura and inflammatory neuropathy. We evaluated recombinant Fc hexamers consisting of the IgM μ-tailpiece fused with the Fc region of human IgG1, without or containing a multimer-stabilizing L309C mutation (Figure 4, top) [51]. Remarkably, the Fc hexamers prevented CDC in AQP4-expressing cells produced by AQP4-IgG and complement with >500-fold greater potency than IVIG or monomeric Fc fragments (Figure 4, bottom). Fc hexamers also efficiently blocked ADCC and prevented NMOSD pathology in rats administered AQP4-IgG by intracerebral injection. Following their approval for other indications, the repurposing of Fc-based therapeutics for prevention and treatment of exacerbations in seropositive NMOSD is appealing because of their predicted favorable safety and efficacy profiles.

Figure 4. Fc hexamers inhibit complement-dependent cytotoxicity in AQP4-expressing cell cultures.

Figure 4.

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Top. Diagram of Fc preparations, including: human immunoglobulin G (IVIG), monomeric Fc fragments (Fc monomers), Fc-μTP (hexameric human IgG1 Fc with 18 amino acid IgM μ-tailpiece fused to the C-terminus of the constant region); and Fc-μTP-L309C (Fc-μTP with stabilizing L309C mutation in the Fc region). Bottom. Complement-dependent cytotoxicity as a function of concentration of indicated Fc preparations. Adapted from ref. [51]. Tradtrantip L, Felix CM, Spirig R, et al. Recombinant IgG1 Fc hexamers block cytotoxicity and pathological changes in experimental in vitro and rat models of neuromyelitis optica. Neuropharmacology. 2018 May 1;133:345–353.

Fc-μTP, recombinant Fc hexamer consisting of the IgM μ-tailpiece fused with the Fc region of human IgG1; Fc-μTP-L309C, Fc-μTP containing a multimer-stabilizing L309C mutationIVIG, intraveneous immunoglobulin.

5. Granulocytes

The presence of granulocytes (neutrophils and eosinophils) as a prominent feature in NMOSD pathology suggests therapeutic benefit of their inhibition or depletion. Pathology in mouse models of seropositive NMOSD is reduced in mice made neutropenic, as well as in mice administered sivelestat, a small molecule inhibitor of neutrophil elastase that is approved in Japan for acute respiratory distress syndrome [52]. A phase I/II clinical trial of sivelestat in acute NMOSD was begun in Japan but discontinued. With regard to eosinophils, in vitro models showed eosinophil-induced killing of AQP4-expressing cells and spinal cord slices exposed to AQP4-IgG, and in vivo models of seropositive NMOSD showed increased pathology in transgenic hypereosinophilic mice and reduced pathology in mice made hypoeosinophilic by IL-5 antibody [53]. Reduced pathology was also seen with the second-generation antihistamine cetirizine, which has eosinophil stabilizing actions. Motivated by these findings, a small clinical pilot study showed safety and potential efficacy of cetirizine in NMOSD [54], though the mg/kg dose used was well below that showing efficacy in mice and predicted to be therapeutically beneficial; perhaps the IL-5 antibody mepolizumab, which is approved for severe asthma [55], would be a better option for eosinophil targeting in NMOSD. In any case, anti-granulocyte therapy might at best be considered for adjunctive therapy of acute disease because of the multiplicity of cellular pathogenesis mechanisms operating in parallel.

6. Blood-brain barrier

As BBB disruption is likely important in the pathogenesis of seropositive NMOSD, drugs that prevent or reverse BBB disruption may be beneficial. Antibodies against endothelial cells have been identified in several autoimmune diseases, including multiple sclerosis, systemic lupus erythematosus and giant cell arteritis [56,57]. These antibodies induce endothelial cell expression of adhesion proteins and proinflammatory cytokines that promote BBB disruption, including IL-1, tumor necrosis factor alpha (TNFα) and vascular endothelial growth factor (VEGF) [58,59]. Sera from some NMOSD patients were found to induce VEGF secretion in human brain microvascular cells and consequent barrier disruption in vitro, which was prevented by an anti-VEGF antibody [60]. Bevacizumab, an anti-VEGF monoclonal antibody that is approved for inhibition of angiogenesis in some cancers, was shown in a phase 1b study in NMOSD to be safe and potentially efficacious [61]. Results of controlled efficacy studies are awaited.

A heat-shock protein, glucose-regulated protein 78 (GRP-78), was identified by a proteomics approach designed to discover endothelial cell targets of autoantibodies in NMOSD patients [20]. GRP-78 autoantibody may promote BBB disruption by NF-κB signaling and reduced expression of claudin-5. GFP-78 is thus a potential target in NMOSD to reduce BBB disruption, though its prevalence, activity, and mechanism in NMOSD require clarification. Several approved drugs reduce BBB disruption via increased claudin-5 expression, including corticosteroids, fingolimod (for relapse-remitting multiple sclerosis) [62]), and perampanel (adjunctive therapy for focal epilepsy) [63]. The potential beneficial actions of various BBB-targeted therapies in NMOSD awaits evaluation (reviewed in ref. [64]).

7. Remyelination

Myelin repair, or remyelination, could in principle rescue function in injured areas of the CNS, provided that there are viable neurons and axons to remyelinate. There is considerable interest, though limited progress, in remyelination therapeutics for multiple sclerosis (reviewed in refs. [65,66]). Therapeutics have been proposed that target different aspects of astrocyte, microglial and neuronal function, with the most logical and promising approaches targeting differentiation and proliferation of oligodendrocyte precursor cells (OPC) to produce mature, myelinating oligodendrocytes. Remyelinating therapeutics at various stages of testing include the LINGO-1 blocker opicinumab, the antihistamine clemastine, mesenchymal stem cells, and others. Remyelination may be particularly challenging in NMOSD compared to multiple sclerosis because of primary astrocyte injury in NMOSD that interferes with important functions of astrocytes in promoting myelination, as well as the highly inflammatory environment that inhibits remyelination and produces irreversible axonal injury. In a proof-of-concept study, an approved drug, clobetasol, was found to promote OPC differentiation in cell culture models and induce remyelination in cerebellar slice cultures and mouse brain in vivo after minor injury with AQP4-IgG and complement [67]. However, it is hard to extrapolate the in vitro and animal models data to human NMOSD because the models are artificial and may not be indicative of the extent of axonal injury and inflammation in human NMOSD. It would seem prudent to await the outcome of remyelination clinical trials in multiple sclerosis prior to consideration of drug repurposing in NMOSD.

8. B cells

B cells are involved in modulating the humoral immune response, with important functions including IgG and cytokine production. B cell abnormalities are thought to occur in NMOSD, perhaps by an imbalance in proinflammatory and anti-inflammatory B cells (reviewed in ref [68]). B cell depletion with the anti-CD20 monoclonal antibody rituximab is generally effective in NMOSD [6]. A newer CD20-targeted drug with enhanced ADCC activity, ublituximab [69], is in a phase 1 clinical trial for NMOSD (NTC02276963). Inebilizumab (MEDI-551), which targets CD19 on B cells as well as on plasma cell and plasmablasts, showed efficacy in a completed phase 3 clinical trial. Compared with placebo, inebilizumab reduced the risk of an NMOSD attack [5].

Targeting B-cell trophic factors such as BAFF (B-cell activation factor) or APRIL (A proliferation inducing ligand) can deplete B cells by CD19/CD20-independent mechanisms that inhibit their proliferation, maturation and survival [70]. The BAFF-targeted monoclonal antibody belimumab is approved for SLE [71] and may be of benefit in NMOSD. Another approach for B cell depletion is adoptive transfer of tandem chimeric antigen receptor (CAR) T-cells, as originally developed for hematopoietic malignancies. Administration of anti-CD19 CAR-T cells improved disease outcome in SLE mice [72], and is under clinical evaluation in NMOSD (NCT03605238).

As an alternative to targeting pro-inflammatory B cells, restoring B cell anti-inflammatory functions is a potential therapeutic strategy in NMOSD. Reduced number and function of B cells that secrete anti-inflammatory cytokines, such as IL-10 and IFN-γ, called “B10 cells”, is reported in some autoimmune diseases including multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus [73]. Adoptive transfer of B10 cells into MRL/Ipr mice protects against glomerular injury and reduces TNF-α and IFN-γ [74]. However, whether B10 cell transfer would be beneficial in NMOSD is not clear, as one study reported reduced B10 cell number during relapse [75] whereas another study reported increased B10 cell number [76].

9. T cells

T cells are involved in elimination of foreign antigens but not self-antigens (self-tolerance). A role for T cell dysregulation in NMOSD is supported by the presence of T cells, including AQP4-reactive T cells, in active NMOSD lesions and the fact that AQP4-IgG is a T cell-dependent IgG subclass [77–79]. Approaches to restore immune tolerance and suppress autoreactive T cells are of potential therapeutic utility in NMOSD. One approach involves inverse DNA vaccination using DNA encoding the T-cell receptor gene of the specific pathogenic T cell. Mice receiving DNA encoding a region of the T-cell receptor involved in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) showed tolerization against MBP autoimmunity [80]. A similar approach restored immune tolerance in a proof of concept study in relapsing-remitting multiple sclerosis [81]. Autoreactive T cell vaccination is another theoretical possibility. An alternative approach to restore tolerance involves regulatory T cells (Tregs), which modulate the function of T cells, B cells and NK cells during self-tolerance immunity [82,83]. Intravenously transferred Tregs showed a beneficial effect in EAE mice, humans with type 1 diabetes, and patients at high risk for graft versus host disease [84–86]. Treg-based therapy is at an early phase in NMOSD in which AQP4-responsive Tregs are in production [83].

As another possible cell-based therapy, dendritic cells (DC) are involved in antigen presentation to immune cells, as well as in the regulation of immune cell responses by release of cytokines and costimulatory signaling [87,88]. Modulation of the anti-inflammatory or tolerogenic functions of DCs has been proposed to be beneficial in NMOSD. Several drugs, including corticosteroids, vitamin D3 and estriol, promote DC tolerance (tolerogenic DCs) [89]. Mice receiving tolerogenic DCs develop less pathology in an EAE model [90]. Intravenously administered autologous DCs, made tolerogenic with corticosteroids, was found to be safe in MS and NMOSD patients, and produced tolerance in peripheral blood mononuclear cells against various peptides including AQP4 peptide [91]. A clinical trial is testing the potential beneficial effects of tolerogenic DCs in MS and NMOSD (NCT02283671).

Lastly, there has been consideration of nonmyeloablative autologous hematopoietic stem cell transplantation in AQP4-IgG seropositive NMOSD. In an open-label study that included 11 AQP4-IgG seropositive NMOSD patients, 9 patients became seronegative and did not have relapses off of immunosuppressant therapy [92].

10. Alternative potential therapeutic targets

Several additional potential targets merit mention. As AQP4 expression at the astrocyte plasma membrane is required for AQP4-IgG-induced activation of CDC and ADCC effector mechanisms, reducing AQP4 expression is predicted to be beneficial in NMOSD. However, at present there is no pharmacological strategy to reduce AQP4 plasma membrane expression, which might act at transcriptional or post-transcriptional levels. Because AQP4-IgG clustering on astrocyte plasma membranes is required to initiate CDC [13], prevention of AQP4 supramolecular association into OAPs or the association of AQP4-bound AQP4-IgG may be beneficial in seropositive NMOSD. Though disruption of AQP4 clustering may not be possible, certain peptides known to disrupt IgG Fc-Fc interactions have been demonstrated to inhibit CDC induced by AQP4-IgG [93]. In addition to the various approaches described herein that target both CDC and ADCC, such as AQP4-IgG inactivation, aquaporumab and Fc multimers, drugs that selectively inhibit ADCC through Fc or other interactions may be beneficial in NMO. With regard to inflammatory mediators involved in various aspects of NMOSD disease pathogenesis, neutralizing antibodies targeting interleukins 4, 5, 6 and 13, as well as TNF, may be beneficial. With regard to B cells involved in the generation of AQP4-IgG, bortezomib, an inhibitor of the 26S proteosome that induces plasma cell apoptosis, has been proposed as an alternative to CD19/CD20-targeted drugs in NMOSD [94].

11. Conclusions

As our understanding of disease pathogenesis mechanisms in AQP4-IgG seropositive NMOSD has advanced remarkably over the past 15 years, so have the number of potential therapeutic target and drug candidates. As summarized in Figure 1, the potential targets include immune cells that generate pathogenic AQP4-IgG autoantibodies, AQP4-IgG itself, AQP4-IgG binding to astrocyte AQP4, components and modulators of complement and cellular cytotoxicity mechanisms, soluble and cellular immune effectors, and downstream remyelination and neuroprotection mechanisms. Additional potential targets include cellular mechanisms involved in AQP4 autoimmunity, the expression and supramolecular assembly of AQP4 on astrocytes, and regulators of blood-brain barrier function. A variety of small-molecule, antibody and cellular therapeutics have emerged, some new while others are already at the investigational or approved stage may be suitable for repurposing in NMOSD.

12. Expert opinion

Immunosuppression, B cell depletion, and plasma exchange have been the standard of care to treat NMOSD, albeit without formal label or rigorous clinical trials data. The recent FDA and EMA approval of eculizumab for seropositive NMOSD, and the anticipated approvals of satralizumab and inebilizumab, offer new therapeutic options to reduce relapse rate and hence cumulative neurological disability. Published data report annualized relapse rates as low as 0.02 with these new drugs [3–5], though the values should be taken cautiously as they depend on trial design, including the study population, relapse criteria and concurrent drug usage. Also, it remains largely unknown the long-term benefit and adverse event profile of these therapeutics being repurposed for NMOSD. Nevertheless, with these favorable outcomes, and the demonstrated efficacy of the standard of care drug rituximab in which a recent meta-analysis of 46 studies reported an approximate 5-fold reduction in annualized relapse rate [6], it is logical to question the necessity for developing and testing of new drugs with alternate targets or mechanisms of action. New therapeutics, as used alone or in combinations, must demonstrate clear-cut advantages in efficacy and/or safety in comparison to standard of care therapies and the newer drugs targeting complement, the IL-6 receptor and CD19.

Notwithstanding the issue of unmet need, the data reviewed herein on disease pathogenesis mechanisms of seropositive NMOSD and novel, early-stage therapeutics suggest a number of interesting new treatment strategies. Prevention of AQP4-IgG binding to AQP4 by an engineered monoclonal anti-AQP4 antibody offers a highly targeted treatment therapeutic approach without the general immunosuppressive effects of most standard of care and newer therapeutics. However, funding the development of a single-disease therapy is challenging, particularly for a rare orphan disease for which available therapies are largely effective [95]. A related challenge is the demonstration of superiority in a comparative clinical trial against drug(s) with an NMOSD label in a relatively heterogeneous patient population.

Autoantibody neutralization by IgG-inactivating enzymes EndoS or IdeS is an intriguing possibility that is gaining attention in several antibody-driven autoimmune conditions. Complement inhibitors in development that target early components of the classical complement pathway, such as C1q and C3, may be highly effective and relatively safe because, unlike eculizumab, they block the generation of anaphylotoxin C3a and do not inhibit bacterial killing though the lectin pathway. Upregulation or activation of astrocyte complement regulator proteins such as CD55 and CD59 is another interesting targeted strategy, which may be particularly beneficial when combined with NMOSD drugs acting by different mechanisms. Multimeric Fc-based drugs such as the Fc hexamers described herein could be highly efficacious as they offer multiple beneficial anti-inflammatory actions, including inhibition of CDC and ADCC, the two major effector mechanisms of astrocyte cytotoxicity.

Many drug candidates that may benefit NMOSD are in development for various non-NMOSD indications, such as Fc multimers, complement inhibitors, and remyelinating drugs. It may be prudent to await their evaluation in NMOSD following approval for non-NMOSD indications. Finally, the ultimate goal of a single-shot cure for NMOSD, perhaps involving AQP4 immune tolerization by vaccination, is an attractive, albeit distant future possibility that warrants continued research, as seropositive NMOSD is a unique, prototypic autoimmune disease with a physically small, defined target, AQP4, and a well-understood pathogenesis mechanism.

As research advances in NMOSD pathogenesis mechanisms and experimental animal models, new therapeutic targets and strategies may emerge, perhaps in immune cell and neuroprotection mechanisms. Though the focus of this review has been on AQP4-IgG seropositive NMOSD, many of the therapeutic strategies discussed herein may be of benefit in treatment of AQP4-IgG seronegative NMOSD as well as other neuroinflammatory diseases, which in general are much less understood than AQP4-IgG seropositive NMOSD in their disease pathogenesis mechanisms.

Article Highlights.

  • Neuromyelitis optica spectrum disorders (NMOSD) are an inflammatory demyelinating disease of the central nervous system that primarily affects spinal cord and optic nerve.

  • Pathogenesis of AQP4-IgG autoantibody seropositive NMOSD involves AQP4-IgG binding to astrocyte AQP4, which causes astrocyte injury and downstream inflammation and demyelination.

  • Conventional therapy for NMOSD includes immunosuppression, B cell depletion and plasma exchange, while newer therapies target complement, CD19 and IL-6 receptors.

  • Potential new therapeutic targets include pathogenic AQP4-IgG autoantibodies and their binding to AQP4, complement-dependent and cellular cytotoxicity, blood-brain barrier, remyelination and immune effector and regulatory cells.

  • Potential future therapeutics include IgG inactivating enzymes, aquaporumab blocking antibodies, drugs targeting early components of the complement pathway, complement regulator-targeted drugs, and Fc-based multimeric compounds.

  • Advancement of various pre-clinical drug candidate may offer therapeutic benefit, with greater efficacy in preventing relapses and reduce side effects.

Acknowledgments

Funding

The work of the authors was funded by the National Institutes of Health (NIH) and Guthy-Jackson Charitable Foundation.

Abbreviations:

ADCC

antibody-dependent cellular cytotoxicity

APRIL

A proliferation inducing ligand

AQP4

aquaporin-4

AQP4-IgG

AQP4-immunoglobulin G

BBB

blood-brain barrier

BAFF

B-cell activation factor

CAR

chimeric antigen receptor

CDC

complement-dependent cytotoxicity

CNS

central nervous system

DC

dendritic cell

EAE

experimental autoimmune encephalomyelitis

EndoS

endoglycosidase S

FcRn

neonatal Fc receptor

GRP-78

glucose-regulated protein 78

IdeS

IgG-degrading enzyme of Streptococcus pyogenes

IVIG

intravenous human immunoglobulin G

GRP-78

glucose-regulated protein 78

MAC

membrane attack complex

NMOSD

neuromyelitis optica spectrum disorder

OAP

orthogonal arrays of particles

OPC

oligodendrocyte precursor cells

TNFα

tumor necrosis factor alpha

Treg

regulatory T cell

VEGF

vascular endothelial growth factor

Footnotes

Declaration of interest

L Tradtrantip is an inventor on patent applications on enzymatic deglycosylation and Fc hexamer therapeutics in NMOSD. The IP is owned by the University of California. AS Verkman is the named inventor on patent applications on aquaporumab antibodies, C1 complement inhibitors, enzymatic deglycosylation and Fc hexamer therapeutics in NMOSD. The IP is owned by the University of California. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

One reviewer was a site PI for the agent inebilizumab, but only received funding for the research activities related to the trial. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose

References

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