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Human Molecular Genetics, 2003, Vol. 12, No. 11 1233-1239
DOI: 10.1093/hmg/ddg143
© 2003 Oxford University Press

Therapeutic benefits of cardiotrophin-1 gene transfer in a mouse model of spinal muscular atrophy

Jeanne-Claire Lesbordes1, Carmen Cifuentes-Diaz2, Audrey Miroglio2, Vandana Joshi2, Thierry Bordet1,{dagger}, Axel Kahn1 and Judith Melki2,*

1Cochin Institute, Department of Genetics, Development and Molecular Pathology, INSERM, CNRS and University René Descartes, 24 rue du Faubourg St Jacques, 75014 Paris, France and 2Molecular Neurogenetics Laboratory, Institut National de la Santé et de la Recherche Médicale (INSERM), University of Evry, E0223, Genopole, 91057 Evry, France

Received February 4, 2003; Accepted March 27, 2003

Spinal muscular atrophy (SMA) is a recessive autosomal disorder characterized by degeneration of lower motor neurons caused by mutations of the survival motor neuron gene (SMN1). No curative treatment is known so far. Mutant mice carrying homozygous deletion of Smn exon 7 directed to neurons display skeletal muscle denervation, moderate loss of motor neuron cell bodies and severe axonal degeneration. These features, similar to those found in human SMA, strongly suggest the involvement of a dying back process of motor neurons and led us to test whether neurotrophic factors might have a protective role in SMA. We report here the therapeutic benefits of systemic delivery of cardiotrophin-1 (CT-1), a neurotrophic factor belonging to the IL-6 cytokine family. Intra-muscular injection of adenoviral vector expressing CT-1, even at very low dose, improves median survival, delays motor defect of mutant mice and exerts protective effect against loss of proximal motor axons and aberrant cytoskeletal organization of motor synaptic terminals. In spite of the severity of SMA phenotype in mutant mice, CT-1 is able to slow down disease progression. Neuroprotection could be regarded as valuable therapeutic approach in SMA.

* To whom correspondence should be addressed at: Molecular Neurogenetics Laboratory, INSERM, University of Evry, E0223, Genopole, 2 rue Gaston Crémieux, CP5724, 91057 Evry, France. Tel: +33 160874552; Fax: +33 160874550; Email: j.melki{at}genopole.inserm.fr

{dagger} Present address: Trophos, Parc Scientifique de Luminy, case 931, 13288 Marseille cedex 9, France.


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