Homologous Recombination Mediates Functional Recovery of Dysferlin Deficiency following AAV5 Gene Transfer
Open accessAbstract
The dysferlinopathies comprise a group of untreatable muscle disorders including limb girdle muscular dystrophy type 2B, Miyoshi myopathy, distal anterior compartment syndrome, and rigid spine syndrome. As with other forms of muscular dystrophy, adeno-associated virus (AAV) gene transfer is a particularly auspicious treatment strategy, however the size of the DYSF cDNA (6.5 kb) negates packaging into traditional AAV serotypes known to express well in muscle (i.e. rAAV1, 2, 6, 8, 9). Potential advantages of a full cDNA versus a mini-gene include: maintaining structural-functional protein domains, evading protein misfolding, and avoiding novel epitopes that could be immunogenic. AAV5 has demonstrated unique plasticity with regards to packaging capacity and recombination of virions containing homologous regions of cDNA inserts has been implicated in the generation of full-length transcripts. Herein we show for the first time in vivo that homologous recombination following AAV5.DYSF gene transfer leads to the production of full length transcript and protein. Moreover, gene transfer of full-length dysferlin protein in dysferlin deficient mice resulted in expression levels sufficient to correct functional deficits in the diaphragm and importantly in skeletal muscle membrane repair. Intravascular regional gene transfer through the femoral artery produced high levels of transduction and enabled targeting of specific muscle groups affected by the dysferlinopathies setting the stage for potential translation to clinical trials. We provide proof of principle that AAV5 mediated delivery of dysferlin is a highly promising strategy for treatment of dysferlinopathies and has far-reaching implications for the therapeutic delivery of other large genes.
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Overlapping vectors work particularly well in muscle tissue, ameliorating phenotypes linked to Duchenne muscular dystrophy and dysferlinopathies.
“This strategy was shown to work particularly well in muscle tissue, ameliorating phenotypes linked to Duchenne muscular dystrophy (DMD) [43][44][45] and dysferlinopathies [46][47][48].”
From Circumventing the packaging limit of AAV-mediated gene replacement therapy for neurological disorders (2022) · cites this paper as [48]
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- Authors
- Grose, W. E., Clark, K. R., Griffin, D., Malik, V., Shontz, K. M., Montgomery, C. L., Lewis, S., Brown, R. H., Janssen, P. M. L., Mendell, J. R., & Rodino-Klapac, L. R.
- Affiliations
- Nationwide Children's Hospital (US)
- University of Massachusetts Chan Medical School (US)
- The Ohio State University (US)
- Corresponding author
- Mendell, Jerry R.
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2012-06-15
- Volume
- 7
- Issue
- 6
- Pages
- e39233
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3376115
- OpenAlex
- W2165253062
- Cited by
- 76
- References
- 49
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 4 · 2023: 3 · 2022: 2 · 2021: 4 · 2020: 2 · 2019: 5 · 2018: 3 · 2017: 7 · 2016: 7 · 2015: 14 · 2014: 9 · 2013: 9 · 2012: 1
- FWCI
- 6.36
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Nationwide Children's Hospital (UL1RR025755)
- National Institutes of Health (5f32ar055008-03, NS045758)
- National Institute of Neurological Disorders and Stroke (P30NS045758)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (F32 AR055008, 1F32AR055008)
- National Center for Research Resources (UL1RR025755)
- 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 › RNA Interference and Gene Delivery
- Keywords
- dysferlin, dysferlinopathy, AAV5, homologous recombination, gene transfer, limb-girdle muscular dystrophy type 2B, Miyoshi myopathy, rigid spine syndrome, full-length cDNA, muscle membrane repair, diaphragm, gene therapy
- MeSH terms
- Dysferlin, Dependovirus, Genetic Vectors, Humans, Membrane Proteins, Muscle Proteins, Recombination, Genetic, Gene Transfer Techniques
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