Therapeutic benefits of cardiotrophin-1 gene transfer in a mouse model of spinal muscular atrophy.
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.
Lesbordes
Jeanne-Claire
JC
Cochin Institute, Department of Genetics, Development and Molecular Pathology, INSERM, CNRS and University René Descartes, 24 rue du Faubourg St Jacques, 75014 Paris, France.
Cifuentes-Diaz
Carmen
C
Miroglio
Audrey
A
Joshi
Vandana
V
Bordet
Thierry
T
Kahn
Axel
A
Melki
Judith
J
D000818:Animals; D001369:Axons / Q000187:drug effects / Q000473:pathology; D016207:Cytokines / Q000235:genetics* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics; D006801:Humans; D007273:Injections, Intramuscular; D051379:Mice; D008817:Mice, Mutant Strains; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D009469:Neuromuscular Junction / Q000187:drug effects / Q000473:pathology; D010791:Phrenic Nerve / Q000187:drug effects / Q000473:pathology; D015996:Survival Rate
D016207:Cytokines; C092073:cardiotrophin 1