Efficient recovery of dysferlin deficiency by dual adeno-associated vector-mediated gene transfer
Abstract
Deficiency of the dysferlin protein presents as two major clinical phenotypes: limb–girdle muscular dystrophy type 2B and Miyoshi myopathy. Dysferlin is known to participate in membrane repair, providing a potential hypothesis to the underlying pathophysiology of these diseases. The size of the dysferlin cDNA prevents its direct incorporation into an adeno-associated virus (AAV) vector for therapeutic gene transfer into muscle. To bypass this limitation, we split the dysferlin cDNA at the exon 28/29 junction and cloned it into two independent AAV vectors carrying the appropriate splicing sequences. Intramuscular injection of the corresponding vectors into a dysferlin-deficient mouse model led to the expression of full-length dysferlin for at least 1 year. Importantly, systemic injection in the tail vein of the two vectors led to a widespread although weak expression of the full-length protein. Injections were associated with an improvement of the histological aspect of the muscle, a reduction in the number of necrotic fibers, restoration of membrane repair capacity and a global improvement in locomotor activity. Altogether, these data support the use of such a strategy for the treatment of dysferlin deficiency.
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The expression of full-length dysferlin led to improved membrane repair capacity, muscle histology, and muscle function.
“As expected, successful trans-splicing resulted in the expression of full-length dysferlin, leading to improved membrane repair capacity, muscle histology, and muscle function. 63”
From Expressing Transgenes That Exceed the Packaging Capacity of Adeno-Associated Virus Capsids (2016) · cites this paper as [63]
In A/J mice injected intramuscularly with dual rAAV vectors encoding the 5′ and 3′ parts of the dysferlin expression cassette, successful trans-splicing resulted in expression of full-length dysferlin.
“As expected, successful trans-splicing resulted in the expression of full-length dysferlin, leading to improved membrane repair capacity, muscle histology, and muscle function. 63”
From Expressing Transgenes That Exceed the Packaging Capacity of Adeno-Associated Virus Capsids (2016) · cites this paper as [63]
Cites
Defective membrane repair in dysferlin-deficient muscular dystrophy
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Self-citationTrans-splicing vectors expand the utility of adeno-associated virus for gene therapy
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Emerging issues in AAV-mediated in vivo gene therapy
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Oversized AAV Transductifon Is Mediated via a DNA-PKcs-independent, Rad51C-dependent Repair Pathway
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Self-citation
- Authors
- Lostal, W., Bartoli, M., Bourg, N., Roudaut, C., Bentaïb, A., Miyake, K., Guerchet, N., Fougerousse, F., McNeil, P., & Richard, I.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Généthon, CNRS UMR8587 LAMBE 1 , 1, rue de l'Internationale, 91000 Evry , France and
- Augusta University (US)
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 2010-02-13
- Volume
- 19
- Issue
- 10
- Pages
- 1897-1907
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2149644790
- Cited by
- 173
- References
- 5
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 19 · 2023: 6 · 2022: 4 · 2021: 5 · 2020: 11 · 2019: 9 · 2018: 8 · 2017: 16 · 2016: 9 · 2015: 15 · 2014: 15 · 2013: 17 · 2012: 13
- FWCI
- 7.73
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- Jain Foundation
- Fondation pour la Recherche Médicale
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Health Sciences › Medicine › Genetics › Neurogenetic and Muscular Disorders Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Keywords
- dysferlin deficiency, limb-girdle muscular dystrophy type 2B, Miyoshi myopathy, adeno-associated virus vectors, intramuscular injection, membrane repair, muscle necrosis, locomotor function
- MeSH terms
- Dysferlin, Dependovirus, Animals, Crosses, Genetic, Female, Genetic Vectors, Injections, Intramuscular, Male, Membrane Proteins, Membranes, Mice, Inbred C57BL, Muscle Proteins, Mutation, Phenotype, Wound Healing, Genetic Therapy, Gene Transfer Techniques, Muscle, Skeletal, Transgenes, Muscular Dystrophies, Limb-Girdle, Mice
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