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Human Molecular Genetics, 2001, Vol. 10, No. 18 1925-1933
© 2001 Oxford University Press

Protective effects of cardiotrophin-1 adenoviral gene transfer on neuromuscular degeneration in transgenic ALS mice

Thierry Bordet, Jeanne-Claire Lesbordes, Saïd Rouhani1, Laëtitia Castelnau-Ptakhine, Henning Schmalbruch2, Georg Haase3 and Axel Kahn+

Département de Génétique, Institut Cochin de Génétique Moléculaire, 24, rue du Fg Saint Jacques, 75014 Paris, France, 1Service d’exploration fonctionnelle, Hopital Cochin, 75014 Paris, France, 2Institute of Medical Physiology, Panum Institute, University of Copenhagen, 2200 Copenhagen N, Denmark and 3INSERM U382, Institut de Biologie du Développement de Marseille, 13288 Marseille, France

Amyotrophic lateral sclerosis (ALS) is mainly a sporadic neurodegenerative disorder characterized by loss of cortical and spinal motoneurons. Some familial ALS cases (FALS) have been linked to dominant mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1). Transgenic mice overexpressing a mutated form of human SOD1 with a Gly93Ala substitution develop progressive muscle wasting and paralysis as a result of spinal motoneuron loss and die at 5 to 6 months. We investigated the effects of neurotrophic factor gene delivery in this FALS model. Intramuscular injection of an adenoviral vector encoding cardiotrophin-1 (CT-1) in SOD1G93A newborn mice resulted in systemic delivery of CT-1, supplying motoneurons with a continuous source of trophic factor. CT-1 delayed the onset of motor impairment as assessed in the rotarod test. Axonal degeneration was slowed and skeletal muscle atrophy was largely reduced by CT-1 treatment. By monitoring the amplitude of the evoked motor response, we showed that the time-course of motor impairment was significantly decreased by CT-1 treatment. Thus, adenovirus-mediated gene transfer of neurotrophic factors might delay neurogenic muscular atrophy and progressive neuromuscular deficiency in ALS patients.

+ To whom correspondence should be addressed. Tel: +33 1 44 41 24 24; Fax: +33 1 44 41 24 21; Email: u129-kahn@cochin.inserm.fr Present address: Thierry Bordet, TROPHOS SA, Parc Scientifique de Luminy, 13288 Marseille, France


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