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PTEN Depletion Decreases Disease Severity and Modestly Prolongs Survival in a Mouse Model of Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) is the second most common genetic cause of death in childhood. However, no effective treatment is available to halt disease progression. SMA is caused by mutations in the survival motor neuron 1 (SMN1) gene. We previously reported that PTEN depletion leads to an increas...

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Autores principales: Little, Daniel, Valori, Chiara F, Mutsaers, Chantal A, Bennett, Ellen J, Wyles, Matthew, Sharrack, Basil, Shaw, Pamela J, Gillingwater, Thomas H, Azzouz, Mimoun, Ning, Ke
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4445616/
https://www.ncbi.nlm.nih.gov/pubmed/25369768
http://dx.doi.org/10.1038/mt.2014.209
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author Little, Daniel
Valori, Chiara F
Mutsaers, Chantal A
Bennett, Ellen J
Wyles, Matthew
Sharrack, Basil
Shaw, Pamela J
Gillingwater, Thomas H
Azzouz, Mimoun
Ning, Ke
author_facet Little, Daniel
Valori, Chiara F
Mutsaers, Chantal A
Bennett, Ellen J
Wyles, Matthew
Sharrack, Basil
Shaw, Pamela J
Gillingwater, Thomas H
Azzouz, Mimoun
Ning, Ke
author_sort Little, Daniel
collection PubMed
description Spinal muscular atrophy (SMA) is the second most common genetic cause of death in childhood. However, no effective treatment is available to halt disease progression. SMA is caused by mutations in the survival motor neuron 1 (SMN1) gene. We previously reported that PTEN depletion leads to an increase in survival of SMN-deficient motor neurons. Here, we aimed to establish the impact of PTEN modulation in an SMA mouse model in vivo. Initial experiments using intramuscular delivery of adeno-associated vector serotype 6 (AAV6) expressing shRNA against PTEN in an established mouse model of severe SMA (SMNΔ7) demonstrated the ability to ameliorate the severity of neuromuscular junction pathology. Subsequently, we developed self-complementary AAV9 expressing siPTEN (scAAV9-siPTEN) to allow evaluation of the effect of systemic suppression of PTEN on the disease course of SMA in vivo. Treatment with a single injection of scAAV9-siPTEN at postnatal day 1 resulted in a modest threefold extension of the lifespan of SMNΔ7 mice, increasing mean survival to 30 days, compared to 10 days in untreated mice. Our data revealed that systemic PTEN depletion is an important disease modifier in SMNΔ7 mice, and therapies aimed at lowering PTEN expression may therefore offer a potential therapeutic strategy for SMA.
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spelling pubmed-44456162015-05-29 PTEN Depletion Decreases Disease Severity and Modestly Prolongs Survival in a Mouse Model of Spinal Muscular Atrophy Little, Daniel Valori, Chiara F Mutsaers, Chantal A Bennett, Ellen J Wyles, Matthew Sharrack, Basil Shaw, Pamela J Gillingwater, Thomas H Azzouz, Mimoun Ning, Ke Mol Ther Original Article Spinal muscular atrophy (SMA) is the second most common genetic cause of death in childhood. However, no effective treatment is available to halt disease progression. SMA is caused by mutations in the survival motor neuron 1 (SMN1) gene. We previously reported that PTEN depletion leads to an increase in survival of SMN-deficient motor neurons. Here, we aimed to establish the impact of PTEN modulation in an SMA mouse model in vivo. Initial experiments using intramuscular delivery of adeno-associated vector serotype 6 (AAV6) expressing shRNA against PTEN in an established mouse model of severe SMA (SMNΔ7) demonstrated the ability to ameliorate the severity of neuromuscular junction pathology. Subsequently, we developed self-complementary AAV9 expressing siPTEN (scAAV9-siPTEN) to allow evaluation of the effect of systemic suppression of PTEN on the disease course of SMA in vivo. Treatment with a single injection of scAAV9-siPTEN at postnatal day 1 resulted in a modest threefold extension of the lifespan of SMNΔ7 mice, increasing mean survival to 30 days, compared to 10 days in untreated mice. Our data revealed that systemic PTEN depletion is an important disease modifier in SMNΔ7 mice, and therapies aimed at lowering PTEN expression may therefore offer a potential therapeutic strategy for SMA. Nature Publishing Group 2015-02 2015-01-06 /pmc/articles/PMC4445616/ /pubmed/25369768 http://dx.doi.org/10.1038/mt.2014.209 Text en Copyright © 2015 American Society of Gene & Cell Therapy http://creativecommons.org/licenses/by/3.0/ This work is licensed under a Creative Commons Attribution 3.0 Unported License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/3.0/
spellingShingle Original Article
Little, Daniel
Valori, Chiara F
Mutsaers, Chantal A
Bennett, Ellen J
Wyles, Matthew
Sharrack, Basil
Shaw, Pamela J
Gillingwater, Thomas H
Azzouz, Mimoun
Ning, Ke
PTEN Depletion Decreases Disease Severity and Modestly Prolongs Survival in a Mouse Model of Spinal Muscular Atrophy
title PTEN Depletion Decreases Disease Severity and Modestly Prolongs Survival in a Mouse Model of Spinal Muscular Atrophy
title_full PTEN Depletion Decreases Disease Severity and Modestly Prolongs Survival in a Mouse Model of Spinal Muscular Atrophy
title_fullStr PTEN Depletion Decreases Disease Severity and Modestly Prolongs Survival in a Mouse Model of Spinal Muscular Atrophy
title_full_unstemmed PTEN Depletion Decreases Disease Severity and Modestly Prolongs Survival in a Mouse Model of Spinal Muscular Atrophy
title_short PTEN Depletion Decreases Disease Severity and Modestly Prolongs Survival in a Mouse Model of Spinal Muscular Atrophy
title_sort pten depletion decreases disease severity and modestly prolongs survival in a mouse model of spinal muscular atrophy
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4445616/
https://www.ncbi.nlm.nih.gov/pubmed/25369768
http://dx.doi.org/10.1038/mt.2014.209
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