Microdystrophin Gene Addition Significantly Improves Muscle Functionality and Diaphragm Muscle Histopathology in a Fibrotic Mouse Model of Duchenne Muscular Dystrophy
Duchenne muscular dystrophy (DMD) is a rare neuromuscular disease affecting 1:5000 newborn males. No cure is currently available, but gene addition therapy, based on the adeno-associated viral (AAV) vector-mediated delivery of microdystrophin transgenes, is currently being tested in clinical trials....
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MDPI AG
2023-05-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/9/8174 |
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| author | Viktorija Cernisova Ngoc Lu-Nguyen Jessica Trundle Shan Herath Alberto Malerba Linda Popplewell |
| author_facet | Viktorija Cernisova Ngoc Lu-Nguyen Jessica Trundle Shan Herath Alberto Malerba Linda Popplewell |
| author_sort | Viktorija Cernisova |
| collection | DOAJ |
| description | Duchenne muscular dystrophy (DMD) is a rare neuromuscular disease affecting 1:5000 newborn males. No cure is currently available, but gene addition therapy, based on the adeno-associated viral (AAV) vector-mediated delivery of microdystrophin transgenes, is currently being tested in clinical trials. The muscles of DMD boys present significant fibrotic and adipogenic tissue deposition at the time the treatment starts. The presence of fibrosis not only worsens the disease pathology, but also diminishes the efficacy of gene therapy treatments. To gain an understanding of the efficacy of AAV-based microdystrophin gene addition in a relevant, fibrotic animal model of DMD, we conducted a systemic study in juvenile <i>D2.mdx</i> mice using the single intravenous administration of an AAV8 system expressing a sequence-optimized murine microdystrophin, named MD1 (AAV8-MD1). We mainly focused our study on the diaphragm, a respiratory muscle that is crucial for DMD pathology and that has never been analyzed after treatment with AAV-microdystrophin in this mouse model. We provide strong evidence here that the delivery of AAV8-MD1 provides significant improvement in body-wide muscle function. This is associated with the protection of the hindlimb muscle from contraction-induced damage and the prevention of fibrosis deposition in the diaphragm muscle. Our work corroborates the observation that the administration of gene therapy in DMD is beneficial in preventing muscle fibrosis. |
| first_indexed | 2024-03-11T04:16:13Z |
| format | Article |
| id | doaj.art-72b7832e602d4d8d822ed9b6eec6cd5d |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T04:16:13Z |
| publishDate | 2023-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-72b7832e602d4d8d822ed9b6eec6cd5d2023-11-17T23:05:58ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-05-01249817410.3390/ijms24098174Microdystrophin Gene Addition Significantly Improves Muscle Functionality and Diaphragm Muscle Histopathology in a Fibrotic Mouse Model of Duchenne Muscular DystrophyViktorija Cernisova0Ngoc Lu-Nguyen1Jessica Trundle2Shan Herath3Alberto Malerba4Linda Popplewell5Department of Biological Sciences, School of Life Sciences and the Environment, Royal Holloway University of London, Egham, Surrey TW20 0EX, UKDepartment of Biological Sciences, School of Life Sciences and the Environment, Royal Holloway University of London, Egham, Surrey TW20 0EX, UKDepartment of Biological Sciences, School of Life Sciences and the Environment, Royal Holloway University of London, Egham, Surrey TW20 0EX, UKDepartment of Biological Sciences, School of Life Sciences and the Environment, Royal Holloway University of London, Egham, Surrey TW20 0EX, UKDepartment of Biological Sciences, School of Life Sciences and the Environment, Royal Holloway University of London, Egham, Surrey TW20 0EX, UKDepartment of Biological Sciences, School of Life Sciences and the Environment, Royal Holloway University of London, Egham, Surrey TW20 0EX, UKDuchenne muscular dystrophy (DMD) is a rare neuromuscular disease affecting 1:5000 newborn males. No cure is currently available, but gene addition therapy, based on the adeno-associated viral (AAV) vector-mediated delivery of microdystrophin transgenes, is currently being tested in clinical trials. The muscles of DMD boys present significant fibrotic and adipogenic tissue deposition at the time the treatment starts. The presence of fibrosis not only worsens the disease pathology, but also diminishes the efficacy of gene therapy treatments. To gain an understanding of the efficacy of AAV-based microdystrophin gene addition in a relevant, fibrotic animal model of DMD, we conducted a systemic study in juvenile <i>D2.mdx</i> mice using the single intravenous administration of an AAV8 system expressing a sequence-optimized murine microdystrophin, named MD1 (AAV8-MD1). We mainly focused our study on the diaphragm, a respiratory muscle that is crucial for DMD pathology and that has never been analyzed after treatment with AAV-microdystrophin in this mouse model. We provide strong evidence here that the delivery of AAV8-MD1 provides significant improvement in body-wide muscle function. This is associated with the protection of the hindlimb muscle from contraction-induced damage and the prevention of fibrosis deposition in the diaphragm muscle. Our work corroborates the observation that the administration of gene therapy in DMD is beneficial in preventing muscle fibrosis.https://www.mdpi.com/1422-0067/24/9/8174Duchenne muscular dystrophymuscle pathologyAAV8-microdystrophinfibrosis |
| spellingShingle | Viktorija Cernisova Ngoc Lu-Nguyen Jessica Trundle Shan Herath Alberto Malerba Linda Popplewell Microdystrophin Gene Addition Significantly Improves Muscle Functionality and Diaphragm Muscle Histopathology in a Fibrotic Mouse Model of Duchenne Muscular Dystrophy International Journal of Molecular Sciences Duchenne muscular dystrophy muscle pathology AAV8-microdystrophin fibrosis |
| title | Microdystrophin Gene Addition Significantly Improves Muscle Functionality and Diaphragm Muscle Histopathology in a Fibrotic Mouse Model of Duchenne Muscular Dystrophy |
| title_full | Microdystrophin Gene Addition Significantly Improves Muscle Functionality and Diaphragm Muscle Histopathology in a Fibrotic Mouse Model of Duchenne Muscular Dystrophy |
| title_fullStr | Microdystrophin Gene Addition Significantly Improves Muscle Functionality and Diaphragm Muscle Histopathology in a Fibrotic Mouse Model of Duchenne Muscular Dystrophy |
| title_full_unstemmed | Microdystrophin Gene Addition Significantly Improves Muscle Functionality and Diaphragm Muscle Histopathology in a Fibrotic Mouse Model of Duchenne Muscular Dystrophy |
| title_short | Microdystrophin Gene Addition Significantly Improves Muscle Functionality and Diaphragm Muscle Histopathology in a Fibrotic Mouse Model of Duchenne Muscular Dystrophy |
| title_sort | microdystrophin gene addition significantly improves muscle functionality and diaphragm muscle histopathology in a fibrotic mouse model of duchenne muscular dystrophy |
| topic | Duchenne muscular dystrophy muscle pathology AAV8-microdystrophin fibrosis |
| url | https://www.mdpi.com/1422-0067/24/9/8174 |
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