An AAV-SGCG Dose-Response Study in a γ-Sarcoglycanopathy Mouse Model in the Context of Mechanical Stress
Sarcoglycanopathies are rare autosomic limb girdle muscular dystrophies caused by mutations in one of the genes coding for sarcoglycans. Sarcoglycans form a complex, which is an important part of the dystrophin-associated glycoprotein complex and which protects the sarcolemma against muscle contract...
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doaj-ee8e06cdf9eb4628b70c764a33633dd62020-11-25T01:09:10ZengElsevierMolecular Therapy: Methods & Clinical Development2329-05012019-06-0113494502An AAV-SGCG Dose-Response Study in a γ-Sarcoglycanopathy Mouse Model in the Context of Mechanical StressDavid Israeli0Jérémie Cosette1Guillaume Corre2Fatima Amor3Jérôme Poupiot4Daniel Stockholm5Marie Montus6Bernard Gjata7Isabelle Richard8INTEGRARE, Généthon, INSERM, Université Evry, Université Paris-Saclay, 91002 Evry, FranceINTEGRARE, Généthon, INSERM, Université Evry, Université Paris-Saclay, 91002 Evry, FranceINTEGRARE, Généthon, INSERM, Université Evry, Université Paris-Saclay, 91002 Evry, FranceINTEGRARE, Généthon, INSERM, Université Evry, Université Paris-Saclay, 91002 Evry, FranceINTEGRARE, Généthon, INSERM, Université Evry, Université Paris-Saclay, 91002 Evry, FranceINTEGRARE, Généthon, INSERM, Université Evry, Université Paris-Saclay, 91002 Evry, FranceINTEGRARE, Généthon, INSERM, Université Evry, Université Paris-Saclay, 91002 Evry, FranceINTEGRARE, Généthon, INSERM, Université Evry, Université Paris-Saclay, 91002 Evry, FranceINTEGRARE, Généthon, INSERM, Université Evry, Université Paris-Saclay, 91002 Evry, France; Corresponding author: Isabelle Richard, INTEGRARE, Généthon, INSERM, Université Evry, Université Paris-Saclay, 1 rue de l’Internationale, 91000 Evry, France.Sarcoglycanopathies are rare autosomic limb girdle muscular dystrophies caused by mutations in one of the genes coding for sarcoglycans. Sarcoglycans form a complex, which is an important part of the dystrophin-associated glycoprotein complex and which protects the sarcolemma against muscle contraction-induced damage. Absence of one of the sarcoglycans on the plasma membrane reduces the stability of the whole complex and perturbs muscle fiber membrane integrity. There is currently no curative treatment for any of the sarcoglycanopathies. A first clinical trial to evaluate the safety of a recombinant AAV2/1 vector expressing γ-sarcoglycan using an intramuscular route of administration showed limited expression of the transgene and good tolerance of the approach. In this report, we undertook a dose-effect study in mice to evaluate the efficiency of an AAV2/8-expressing γ-sarcoglycan controlled by a muscle-specific promoter with a systemic mode of administration. We observed a dose-related efficiency with a nearly complete restoration of gamma sarcoglycan (SGCG) expression, histological appearance, biomarker level, and whole-body strength at the highest dose tested. In addition, our data suggest that a high expression threshold level must be achieved for effective protection of the transduced muscle, while a suboptimal transgene expression level might be less protective in the context of mechanical stress. Keywords: LGMD2C, γ-sarcoglycanopathy, limb girdle muscular dystrophy, gene therapy, translational medicine, AAV, miRNA biomarker, mechanical stresshttp://www.sciencedirect.com/science/article/pii/S2329050119300439 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
David Israeli Jérémie Cosette Guillaume Corre Fatima Amor Jérôme Poupiot Daniel Stockholm Marie Montus Bernard Gjata Isabelle Richard |
spellingShingle |
David Israeli Jérémie Cosette Guillaume Corre Fatima Amor Jérôme Poupiot Daniel Stockholm Marie Montus Bernard Gjata Isabelle Richard An AAV-SGCG Dose-Response Study in a γ-Sarcoglycanopathy Mouse Model in the Context of Mechanical Stress Molecular Therapy: Methods & Clinical Development |
author_facet |
David Israeli Jérémie Cosette Guillaume Corre Fatima Amor Jérôme Poupiot Daniel Stockholm Marie Montus Bernard Gjata Isabelle Richard |
author_sort |
David Israeli |
title |
An AAV-SGCG Dose-Response Study in a γ-Sarcoglycanopathy Mouse Model in the Context of Mechanical Stress |
title_short |
An AAV-SGCG Dose-Response Study in a γ-Sarcoglycanopathy Mouse Model in the Context of Mechanical Stress |
title_full |
An AAV-SGCG Dose-Response Study in a γ-Sarcoglycanopathy Mouse Model in the Context of Mechanical Stress |
title_fullStr |
An AAV-SGCG Dose-Response Study in a γ-Sarcoglycanopathy Mouse Model in the Context of Mechanical Stress |
title_full_unstemmed |
An AAV-SGCG Dose-Response Study in a γ-Sarcoglycanopathy Mouse Model in the Context of Mechanical Stress |
title_sort |
aav-sgcg dose-response study in a γ-sarcoglycanopathy mouse model in the context of mechanical stress |
publisher |
Elsevier |
series |
Molecular Therapy: Methods & Clinical Development |
issn |
2329-0501 |
publishDate |
2019-06-01 |
description |
Sarcoglycanopathies are rare autosomic limb girdle muscular dystrophies caused by mutations in one of the genes coding for sarcoglycans. Sarcoglycans form a complex, which is an important part of the dystrophin-associated glycoprotein complex and which protects the sarcolemma against muscle contraction-induced damage. Absence of one of the sarcoglycans on the plasma membrane reduces the stability of the whole complex and perturbs muscle fiber membrane integrity. There is currently no curative treatment for any of the sarcoglycanopathies. A first clinical trial to evaluate the safety of a recombinant AAV2/1 vector expressing γ-sarcoglycan using an intramuscular route of administration showed limited expression of the transgene and good tolerance of the approach. In this report, we undertook a dose-effect study in mice to evaluate the efficiency of an AAV2/8-expressing γ-sarcoglycan controlled by a muscle-specific promoter with a systemic mode of administration. We observed a dose-related efficiency with a nearly complete restoration of gamma sarcoglycan (SGCG) expression, histological appearance, biomarker level, and whole-body strength at the highest dose tested. In addition, our data suggest that a high expression threshold level must be achieved for effective protection of the transduced muscle, while a suboptimal transgene expression level might be less protective in the context of mechanical stress. Keywords: LGMD2C, γ-sarcoglycanopathy, limb girdle muscular dystrophy, gene therapy, translational medicine, AAV, miRNA biomarker, mechanical stress |
url |
http://www.sciencedirect.com/science/article/pii/S2329050119300439 |
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