Systemic administration of a recombinant AAV1 vector encoding IGF-1 improves disease manifestations in SMA mice
Journal
Molecular Therapy
Journal Volume
22
Journal Issue
8
Pages
1450-1459
Date Issued
2014
Author(s)
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. ? The American Society of Gene & Cell Therapy.
SDGs
Other Subjects
parvovirus vector; recombinant somatomedin C; somatomedin C; somatomedin C; survival motor neuron protein; survival motor neuron protein 2; IGF1 protein, human; Smn1 protein, mouse; somatomedin C; survival motor neuron protein 1; adult; animal experiment; animal model; animal tissue; article; body weight; controlled study; drug efficacy; drug muscle level; drug safety; enzyme release; human; lifespan; motor coordination; mouse; nerve cell degeneration; neuromuscular synapse; newborn; nonhuman; protein expression; real time polymerase chain reaction; spinal muscular atrophy; systemic therapy; Western blotting; Article; brain; heart; liver; motoneuron; mouse model; muscle atrophy; nerve degeneration; polymerase chain reaction; spinal cord; weight gain; administration and dosage; animal; blood; Dependoparvovirus; disease model; gene therapy; gene vector; genetics; intravenous drug administration; metabolism; Muscular Atrophy, Spinal; pathophysiology; procedures; treatment outcome; Adeno-associated virus; Animalia; Mus; Animals; Dependovirus; Disease Models, Animal; Genetic Therapy; Genetic Vectors; Humans; Injections, Intravenous; Insulin-Like Growth Factor I; Liver; Mice; Muscular Atrophy, Spinal; Survival of Motor Neuron 1 Protein; Treatment Outcome
Publisher
Nature Publishing Group
Type
journal article