title: Cerebrospinal fluid-targeted delivery of neutralizing anti-IFNγ antibody delays motor decline in an ALS mouse model.
abstract: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the selective and gradual loss of motoneurons in the brain and spinal cord. A persistent inflammation, typified by the activation of astrocytes and microglia, accompanies the progressive degeneration of motoneurons. Interferon gamma (IFNγ), a potent proinflammatory cytokine that is aberrantly present in the spinal cord of ALS mice and patients, has been proposed to contribute to motoneuron death by eliciting the activation of the lymphotoxin-β receptor (LT-βR) through its ligand LIGHT. However, the implication of IFNγ in the pathogenic process remains elusive. Here, we show that an antagonistic anti-IFNγ antibody efficiently rescues motoneurons from IFNγ-induced death. When transiently delivered in the cerebrospinal fluid through a subcutaneously implanted osmotic minipump, the neutralizing anti-IFNγ antibody significantly retarded motor function decline in a mouse model of ALS. However, this transient infusion of anti-IFNγ antibody did not increase the life expectancy of ALS mice. Our results suggest that IFNγ contributes to ALS pathogenesis and represents a potential therapeutic target for ALS.
authors.affiliation: aMediterranean Institute of Neurobiology, INMED, INSERM U901, Marseille bNeuroscience Institute Montpellier (INM), INSERM UMR1051, Saint Eloi Hospital, Montpellier, France cNeurodegenerative Studies Laboratory, Brain Mind Institute, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
authors.forename: Belkacem
authors.initials: B
authors.lastname: Otsmane
authors.forename: Julianne
authors.initials: J
authors.lastname: Aebischer
authors.forename: Anice
authors.initials: A
authors.lastname: Moumen
authors.forename: Cédric
authors.initials: C
authors.lastname: Raoul
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology / Q000627:therapeutic use*; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D007371:Interferon-gamma / Q000276:immunology*; D051379:Mice; D009043:Motor Activity / Q000187:drug effects* / Q000276:immunology; D009046:Motor Neurons / Q000187:drug effects* / Q000276:immunology
chemical_list: D057134:Antibodies, Neutralizing; D007371:Interferon-gamma