Systemic Administration of a Recombinant AAV1 Vector Encoding IGF-1 Improves Disease Manifestations in SMA Mice

• Published in: Molecular therapy 2014-08, Vol.22 (8), p.1450-1459
• Main Authors: Tsai, Li-Kai, Chen, Chien-Lin, Ting, Chen-Hung, Lin-Chao, Sue, Hwu, Wuh-Liang, Dodge, James C, Passini, Marco A, Cheng, Seng H
• Format: Article
• Language: English
• Subjects: Adeno-associated virus; Animals; Atrophy; Dependovirus - genetics; Disease Models, Animal; Genetic Therapy - methods; Genetic Vectors - administration & dosage; Heart; Hospitals; Humans; Injections, Intravenous; Insulin; Insulin-Like Growth Factor I - administration & dosage; Insulin-Like Growth Factor I - genetics; Insulin-like growth factors; Liver; Liver - metabolism; Mice; Motor neurone disease; Muscular Atrophy, Spinal - blood; Muscular Atrophy, Spinal - genetics; Muscular Atrophy, Spinal - physiopathology; Muscular Atrophy, Spinal - therapy; Musculoskeletal system; Original; Polymerase chain reaction; Proteins; Spinal cord; Survival of Motor Neuron 1 Protein - genetics; Survival of Motor Neuron 1 Protein - metabolism; Treatment Outcome; Veins & arteries
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1038/mt.2014.84

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.