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AAV9-Mediated Expression of SMN Restricted to Neurons Does Not Rescue the Spinal Muscular Atrophy Phenotype in Mice

Abstract : Spinal muscular atrophy (SMA) is a neuromuscular disease mainly caused by mutations or deletions in the survival of motor neuron 1 (SMN1) gene and characterized by the degeneration of motor neurons and progressive muscle weakness. A viable therapeutic approach for SMA patients is a gene replacement strategy that restores functional SMN expression using adenoassociated virus serotype 9 (AAV9) vectors. Currently, systemic or intra-cerebrospinal fluid (CSF) delivery of AAV9-SMN is being explored in clinical trials. In this study, we show that the postnatal delivery of an AAV9 that expresses SMN under the control of the neuron-specific promoter synapsin selectively targets neurons without inducing re-expression in the peripheral organs of SMA mice. However, this approach is less efficient in restoring the survival and neuromuscular functions of SMA mice than the systemic or intra-CSF delivery of an AAV9 in which SMN is placed under the control of a ubiquitous promoter. This study suggests that further efforts are needed to understand the extent to which SMN is required in neurons and peripheral organs for a successful therapeutic effect.
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https://www.hal.inserm.fr/inserm-03130706
Contributor : Sylvie Dufour <>
Submitted on : Wednesday, February 3, 2021 - 6:14:21 PM
Last modification on : Friday, June 4, 2021 - 11:24:03 AM

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Aurore Besse, Stephanie Astord, Thibaut Marais, Marianne Roda, Benoit Giroux, et al.. AAV9-Mediated Expression of SMN Restricted to Neurons Does Not Rescue the Spinal Muscular Atrophy Phenotype in Mice. Molecular Therapy, Nature Publishing Group, 2020, 28 (8), pp.1887-1901. ⟨10.1016/j.ymthe.2020.05.011⟩. ⟨inserm-03130706⟩

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