Cellular and animal models of antibody-mediated encephalitis: from pathogenesis to novel therapeutics

Abstract

[eng] BACKGROUND:

Antibody-mediated encephalitides represent a novel category of brain inflammatory disorders mediated by antibodies targeting neural cell- surface proteins. The most prevalent form is anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis, characterized by autoantibodies against the GluN1 subunit of NMDAR, leading to severe neuropsychiatric symptoms that often improve with immunotherapy. Unlike conventional brain imaging, diffusion tensor imaging studies have demonstrated extensive white matter changes in patients, as oligodendrocytes are responsible for myelin synthesis and express NMDAR. Most patients experience a slow recovery, with lingering memory and cognitive deficits, and the optimal treatment approach remains unclear. New therapeutic approaches, such as the NMDAR positive allosteric modulator (PAM) SGE-301, should be tested as complementary treatment to immunotherapy. There is a critical need for models that provide a comprehensive neuro-immunobiological understanding of the disease and offer a clinical course long enough to facilitate the assessment of potential new treatments. Another less common form of antibody-mediated encephalitis is anti- metabotropic glutamate receptor 5 (mGluR5) encephalitis. This disorder is less well-characterized, and the effect of patients’ antibodies has not yet been assessed in vivo.

OBJECTIVES:

1) To determine the pathogenicity of the antibodies of patients with anti- mGluR5 encephalitis in a mouse model of cerebroventricular antibody transfer. 2) To investigate the effect of the antibodies of patients with anti-NMDAR encephalitis on cultures of oligodendrocytes. 3) To assess whether SGE-301 prevents and restores the pathological effect of patients’ anti-NMDAR antibodies in a mouse model. 4) To elucidate whether SGE-301 modifies the cell surface dynamics of NMDARs. 5) To develop an animal model of anti-NMDAR encephalitis by active immunization in order to characterize the neuro-immunobiology of the disease and test different treatments, including immunotherapy and SGE-301.