Emerging therapeutic targets for neuromyelitis optica spectrum disorder

ABSTRACT

Introduction: Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory demyelinating disease of the central nervous system affecting primarily the spinal cord and optic nerves. 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

Article Highlights

• Neuromyelitis optica spectrum disorder (NMOSD) is 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 candidates may offer therapeutic benefit, with greater efficacy in preventing relapses and reducing side effects.

This box summarizes key points contained in the article.

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.

Additional information

Funding

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