Human Molecular Genetics, 2002, Vol. 11, No. 14 1615-1625
© 2002 Oxford University Press
In vivo electrotransfer of the cardiotrophin-1 gene into skeletal muscle slows down progression of motor neuron degeneration in pmn mice
1Département de Génétique, Développement et Pathologie Moléculaire, Institut Cochin, INSERM, CNRS, Université René Descartes, 24 rue du Faubourg St Jacques, 75014 Paris, France, 2Institut de Biologie du Développement de Marseille, INSERM U382, 13288 Marseille Cedex 09, France and 3Service d'Exploration Fonctionnelle, CHU Cochin, AP-HP-Université Paris V-27, rue du Faubourg St Jacques, 75014 Paris, France
Received February 6, 2002; Accepted May 1, 2002
Among all vectors designed for gene therapy purposes, adenovirus appears to be the most efficient in vivo vehicle to transduce the broadest spectrum of cellular targets. However, the deleterious immunogenicity of this viral vector impedes its use in chronic diseases. Non-viral vectors, such as naked DNA, are attractive alternatives for safety and technical issues, such as scale-up production. Naked DNA injection, greatly improved when combined with electroporation, showed great potential in adult animals, especially when directed to the muscle. We have recently proven the therapeutic effect of a neonatal single intramuscular injection of a cardiotrophin-1 (CT-1)-encoding adenovirus in a hereditary disease mouse model of human motor neuron disease, the progressive motor neuronopathy (pmn) mutant. We now demonstrate that a single injection/electroporation of a CT-1-encoding plasmid in neonate pmn mice is almost as efficient as adenovirus-mediated gene transfer with respect to survival, muscular function and neuroprotection of the animals. Treated mice gain global weight, their mean lifespan is extended by 25%, all their electromyographic parameters are improved and myelinated axons of their phrenic nerves are protected. Moreover, we show that re-injection/electroporation leads to improvements in this neuroprotection. We therefore demonstrate for the first time the therapeutic efficacy of neonatal intramuscular DNA injection/electroporation in a murine model of a human hereditary disorder.
* To whom correspondence should be addressed. Tel: +33 1 40516457; Fax: +33 1 40516474; Email: kahn{at}cochin.inserm.fr
Present address: TROPHOS, Parc Scientifique de Luminy, case 931, 13288 Marseille cedex 9, France.
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