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

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...

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Autores principales: Besse, Aurore, Astord, Stephanie, Marais, Thibaut, Roda, Marianne, Giroux, Benoit, Lejeune, François-Xavier, Relaix, Frederic, Smeriglio, Piera, Barkats, Martine, Biferi, Maria Grazia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403319/
https://www.ncbi.nlm.nih.gov/pubmed/32470325
http://dx.doi.org/10.1016/j.ymthe.2020.05.011
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author Besse, Aurore
Astord, Stephanie
Marais, Thibaut
Roda, Marianne
Giroux, Benoit
Lejeune, François-Xavier
Relaix, Frederic
Smeriglio, Piera
Barkats, Martine
Biferi, Maria Grazia
author_facet Besse, Aurore
Astord, Stephanie
Marais, Thibaut
Roda, Marianne
Giroux, Benoit
Lejeune, François-Xavier
Relaix, Frederic
Smeriglio, Piera
Barkats, Martine
Biferi, Maria Grazia
author_sort Besse, Aurore
collection PubMed
description 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 adeno-associated 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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spelling pubmed-74033192021-08-05 AAV9-Mediated Expression of SMN Restricted to Neurons Does Not Rescue the Spinal Muscular Atrophy Phenotype in Mice Besse, Aurore Astord, Stephanie Marais, Thibaut Roda, Marianne Giroux, Benoit Lejeune, François-Xavier Relaix, Frederic Smeriglio, Piera Barkats, Martine Biferi, Maria Grazia Mol Ther Original Article 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 adeno-associated 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. American Society of Gene & Cell Therapy 2020-08-05 2020-05-15 /pmc/articles/PMC7403319/ /pubmed/32470325 http://dx.doi.org/10.1016/j.ymthe.2020.05.011 Text en © 2020 The Author(s) http://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Original Article
Besse, Aurore
Astord, Stephanie
Marais, Thibaut
Roda, Marianne
Giroux, Benoit
Lejeune, François-Xavier
Relaix, Frederic
Smeriglio, Piera
Barkats, Martine
Biferi, Maria Grazia
AAV9-Mediated Expression of SMN Restricted to Neurons Does Not Rescue the Spinal Muscular Atrophy Phenotype in Mice
title AAV9-Mediated Expression of SMN Restricted to Neurons Does Not Rescue the Spinal Muscular Atrophy Phenotype in Mice
title_full AAV9-Mediated Expression of SMN Restricted to Neurons Does Not Rescue the Spinal Muscular Atrophy Phenotype in Mice
title_fullStr AAV9-Mediated Expression of SMN Restricted to Neurons Does Not Rescue the Spinal Muscular Atrophy Phenotype in Mice
title_full_unstemmed AAV9-Mediated Expression of SMN Restricted to Neurons Does Not Rescue the Spinal Muscular Atrophy Phenotype in Mice
title_short AAV9-Mediated Expression of SMN Restricted to Neurons Does Not Rescue the Spinal Muscular Atrophy Phenotype in Mice
title_sort aav9-mediated expression of smn restricted to neurons does not rescue the spinal muscular atrophy phenotype in mice
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7403319/
https://www.ncbi.nlm.nih.gov/pubmed/32470325
http://dx.doi.org/10.1016/j.ymthe.2020.05.011
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