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.

CNS Aquaporin‐4‐specific B cells connect with multiple B‐cell compartments in neuromyelitis optica spectrum disorder

“…In 75% of NMOSD patients, autoreactive B cells produce antibodies against the aquaporin‐4 (AQP4) water channel (AQP4‐IgG) 2, 3. In the central nervous system (CNS), AQP4 is highly expressed on astrocyte end‐feet, and AQP4‐IgG has been shown to initiate an inflammatory cascade that ultimately leads to demyelination and neuronal injury 1, 4, 5. However, the location(s) of initial antigen presentation and affinity maturation, as well as the composition of migratory AQP4‐reactive B cells remains largely unknown.…”

Present and Future Therapies in Neuromyelitis Optica Spectrum Disorders

“…While 1 study reported that a monophasic disease course is more common in AQP4-IgG-negative patients [11], this was not found in another study [58]. It is unclear whether AQP4-IgG seronegative and seropositive NMOSD are driven by similar humoral immune mechanisms [29]. Therapeutic recommendations for AQP4-IgG-positive NMOSD cannot bona fide be transferred to seronegative patients, who should be treated on an individual basis, guided by severity and remission of the first attack and the clinical course [8].…”

“…Several other complement inhibitors, for example monoclonal antibodies targeting C1, and compounds inhibiting C1 esterase activity, C3, or C3a and C5a receptors, were assessed in preclinical models or have been suggested for theoretical reasons [29].…”

“…One approach is to block competitively the binding of AQP4-IgG to AQP4 (e.g., by the nonpathogenic human monoclonal antibody aquaporumab); others include enzymatic deglycosylation or cleavage of AQP4-IgG [29]. Furthermore, various techniques to restore immune tolerance to AQP4 derived from animal models and other human autoimmune diseases have been suggested or are in (pre-)clinical development [29,140]. Examples are DNA vaccination [141], T-cell-based vaccines [142], peptide-coupling strategies [143], and adoptive transfer of tolerogenic dendritic cells or regulatory T cells [144].…”

“…With advances in knowledge about the immunopathology of NMOSD [28], innovative therapeutic concepts [29], and the first randomized controlled trials coming up, we are now approaching a new era of NMOSD therapy. In this review, we will discuss present and future immunotherapies for NMOSD.…”