Intramuscular scAAV9-SMN Injection Mediates Widespread Gene Delivery to the Spinal Cord and Decreases Disease Severity in SMA Mice

• Published in: Molecular therapy 2013-02, Vol.21 (2), p.282-290
• Main Authors: Benkhelifa-Ziyyat, Sofia, Besse, Aurore, Roda, Marianne, Duque, Sandra, Astord, Stéphanie, Carcenac, Romain, Marais, Thibaut, Barkats, Martine
• Format: Article
• Language: English
• Subjects: Adeno-associated virus; Animals; Central Nervous System - metabolism; Central Nervous System - pathology; Dependovirus - genetics; Disease; Disease Models, Animal; Efficiency; Gene Expression Regulation; Gene therapy; Gene Transfer Techniques; Genetic Therapy - methods; Genetic Vectors; Injections, Intramuscular; Investigations; Mice; Mice, Transgenic; Motor Neurons - metabolism; Motor Neurons - pathology; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscular Atrophy, Spinal - genetics; Muscular Atrophy, Spinal - pathology; Muscular Atrophy, Spinal - therapy; Nervous system; Neurons; Original; Proteins; Spinal cord; Spinal Cord - metabolism; Spinal Cord - pathology; Transgenes; Vectors (Biology)
• ISSN: 1525-0016; 1525-0024
• DOI: 10.1038/mt.2012.261

We have recently demonstrated the remarkable efficiency of self-complementary (sc) AAV9 vectors for central nervous system (CNS) gene transfer following intravenous delivery in mice and larger animals. Here, we investigated whether gene delivery to motor neurons (MNs) could also be achieved via intramuscular (i.m.) scAAV9 injection and subsequent retrograde transport along the MNs axons. Unexpectedly, we found that a single injection of scAAV9 into the adult mouse gastrocnemius (GA) mediated widespread MN transduction along the whole spinal cord, without limitation to the MNs connected to the injected muscle. Spinal cord astrocytes and peripheral organs were also transduced, indicating vector spread from the injected muscle to both the CNS and the periphery through release into the blood circulation. Moreover, we showed that i.m. injection of scAAV9 vectors expressing “survival of motor neuron” (Smn) in spinal muscular atrophy (SMA) mice mediated high survival motor neuron (SMN) expression levels at both the CNS and the periphery, and increased the median lifespan from 12 days to 163 days. These findings represent to date the longest extent in survival obtained in SMA mice following i.m. viral vector gene delivery, and might generate a renewed interest in the use of i.m. adeno-associated viruses (AAV) delivery for the development of gene therapy strategies for MN diseases.