Protective effects of cardiotrophin-1 adenoviral gene transfer on neuromuscular degeneration in transgenic ALS mice.
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.
Bordet
T
T
Département de Génétique, Institut Cochin de Génétique Moléculaire, 24, rue du Fg Saint Jacques, 75014 Paris, France.
Lesbordes
J C
JC
Rouhani
S
S
Castelnau-Ptakhine
L
L
Schmalbruch
H
H
Haase
G
G
Kahn
A
A
D000256:Adenoviridae / Q000235:genetics; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000503:physiopathology / Q000628:therapy; D000818:Animals; D000831:Animals, Newborn; D001284:Atrophy; D001522:Behavior, Animal / Q000502:physiology; D001835:Body Weight; D016207:Cytokines / Q000235:genetics* / Q000502:physiology; D005260:Female; D015870:Gene Expression; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D006801:Humans; D007273:Injections, Intramuscular; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000473:pathology; D009154:Mutation; D009410:Nerve Degeneration / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D009468:Neuromuscular Diseases / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D009469:Neuromuscular Junction / Q000502:physiology; D010791:Phrenic Nerve / Q000473:pathology; D013482:Superoxide Dismutase / Q000235:genetics; D016019:Survival Analysis; D013997:Time Factors
D016207:Cytokines; C092073:cardiotrophin 1; D013482:Superoxide Dismutase