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Cerebrospinal fluid-targeted delivery of neutralizing anti-IFNγ antibody delays motor decline in an ALS mouse model

Otsmane, Belkacema; Aebischer, Juliannea,c; Moumen, Anicea; Raoul, Cédrica,b

doi: 10.1097/WNR.0000000000000043
DEGENERATION AND REPAIR

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.

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

Correspondence to Cédric Raoul, PhD, Neuroscience Institute Montpellier (INM), INSERM UMR1051, Saint Eloi Hospital, 34091 Montpellier, Cedex 05, France Tel: +33 499 636 115; fax: +33 499 636 020; e-mail: cedric.raoul@inserm.fr

Received August 21, 2013

Accepted September 12, 2013

© 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins