title: Systemic administration of a recombinant AAV1 vector encoding IGF-1 improves disease manifestations in SMA mice.
abstract: Spinal muscular atrophy is a progressive motor neuron disease caused by a deficiency of survival motor neuron. In this study, we evaluated the efficacy of intravenous administration of a recombinant adeno-associated virus (AAV1) vector encoding human insulin-like growth factor-1 (IGF-1) in a severe mouse model of spinal muscular atrophy. Measurable quantities of human IGF-1 transcripts and protein were detected in the liver (up to 3 months postinjection) and in the serum indicating that IGF-1 was secreted from the liver into systemic circulation. Spinal muscular atrophy mice administered AAV1-IGF-1 on postnatal day 1 exhibited a lower extent of motor neuron degeneration, cardiac and muscle atrophy as well as a greater extent of innervation at the neuromuscular junctions compared to untreated controls at day 8 posttreatment. Importantly, treatment with AAV1-IGF-1 prolonged the animals' lifespan, increased their body weights and improved their motor coordination. Quantitative polymerase chain reaction and western blot analyses showed that AAV1-mediated expression of IGF-1 led to an increase in survival motor neuron transcript and protein levels in the spinal cord, brain, muscles, and heart. These data indicate that systemically delivered AAV1-IGF-1 can correct several of the biochemical and behavioral deficits in spinal muscular atrophy mice through increasing tissue levels of survival motor neuron.
authors.affiliation: Department of Neurology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan. Electronic address: milikai@ntuh.gov.tw.
authors.forename: Li-Kai
authors.initials: LK
authors.lastname: Tsai
authors.affiliation: Department of Neurology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Chien-Lin
authors.initials: CL
authors.lastname: Chen
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.
authors.forename: Chen-Hung
authors.initials: CH
authors.lastname: Ting
authors.affiliation: Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.
authors.forename: Sue
authors.initials: S
authors.lastname: Lin-Chao
authors.affiliation: Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Wuh-Liang
authors.initials: WL
authors.lastname: Hwu
authors.affiliation: Genzyme, a Sanofi Company, Framingham, Massachusetts, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Dodge
authors.affiliation: Genzyme, a Sanofi Company, Framingham, Massachusetts, USA.
authors.forename: Marco A
authors.initials: MA
authors.lastname: Passini
authors.affiliation: Genzyme, a Sanofi Company, Framingham, Massachusetts, USA.
authors.forename: Seng H
authors.initials: SH
authors.lastname: Cheng
mesh_terms: D000818:Animals; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D006801:Humans; D007275:Injections, Intravenous; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage / Q000235:genetics*; D008099:Liver / Q000378:metabolism; D051379:Mice; D009134:Muscular Atrophy, Spinal / Q000097:blood / Q000235:genetics / Q000503:physiopathology* / Q000628:therapy*; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: C583557:IGF1 protein, human; C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein; D007334:Insulin-Like Growth Factor I