Résumé :
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Gene therapy for Central Nervous System (CNS) disorders is impeded by the Blood Brain Barrier (BBB), a physical barrier preventing the entry of viral vectors. For motor neuron diseases (e.g. Spinal Muscular Atrophy (SMA) and Amyotrophic Lateral Sclerosis (ALS)), this problem has been previously circumvented by injecting viral vectors directly into the spinal cord. This approach resulted only in the transduction of cells close to the injection site. The development of strategies less invasive and allowing a larger dispersion of viral vectors and/or therapeutic proteins in the CNS is therefore required for future clinical application. Here, we describe a new gene transfer method that allows efficient transduction of lower motor neurons after peripheral injection of recombinant AAV vectors. We first injected single strand (ss) and self-complementary (sc) AAV vectors of serotype 1 and 9 intraperitoneally, intramuscularly or intravenously in neonatal and adult C57Bl6 mice and analyzed transgene expression in the CNS. We found that both recombinant ss- and scAAV9 vectors targeted epithelial cells of both the choroids plexus and the ependyma, as well as neural cells including motor neurons. In mice, the most impressive transduction was observed after intravenous administration of scAAV9 vectors. Futhermore, the ability of scAAV9 to efficiently cross the BBB and transduce motor neurons was confirmed in a feline model of SMA. In these animals, intravenous vector injections led to a transduction of 38% of motor neurons. In conclusion, this study describes the first efficient and non invasive procedure that allows a global transgene delivery to the spinal cord via a single intravenous injection. This new gene therapy tool offers new hope for the treatment of motor neuron diseases.
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