Gene therapy of murine motor neuron disease using adenoviral vectors for neurotrophic factors.
Motor neuron diseases such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy cause progressive paralysis, often leading to premature death. Neurotrophic factors have been suggested as therapeutic agents for motor neuron diseases, but their clinical use as injected recombinant protein was limited by toxicity and/or poor bioavailability. We demonstrate here that adenovirus-mediated gene transfer of neurotrophin-3 (NT-3) can produce substantial therapeutic effects in the mouse mutant pmn (progressive motor neuronopathy). After intramuscular injection of the NT-3 adenoviral vector, pmn mice showed a 50% increase in life span, reduced loss of motor axons and improved neuromuscular function as assessed by electromyography. These results were further improved by coinjecting an adenoviral vector coding for ciliary neurotrophic factor. Therefore, adenovirus-mediated gene transfer of neurotrophic factors offers new prospects for the treatment of motor neuron diseases.
Haase
G
G
INSERM Unit 129, Institut Cochin de Génétique Moleculaire, Paris, France.
Kennel
P
P
Pettmann
B
B
Vigne
E
E
Akli
S
S
Revah
F
F
Schmalbruch
H
H
Kahn
A
A
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D020934:Ciliary Neurotrophic Factor; D004576:Electromyography; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D007273:Injections, Intramuscular; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008817:Mice, Mutant Strains; D016472:Motor Neuron Disease / Q000401:mortality / Q000628:therapy*; D009132:Muscles / Q000294:innervation; D009410:Nerve Degeneration / Q000187:drug effects; D009414:Nerve Growth Factors / Q000235:genetics / Q000627:therapeutic use*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000627:therapeutic use*; D020933:Neurotrophin 3; D010791:Phrenic Nerve / Q000473:pathology; D016019:Survival Analysis
D020934:Ciliary Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D020933:Neurotrophin 3