Systemic AAV-Mediated β-Sarcoglycan Delivery Targeting Cardiac and Skeletal Muscle Ameliorates Histological and Functional Deficits in LGMD2E Mice
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Limb-girdle muscular dystrophy type 2E (LGMD2E), resulting from mutations in β-sarcoglycan ( SGCB ), is a progressive dystrophy with deteriorating muscle function, respiratory failure, and cardiomyopathy in 50% or more of LGMD2E patients. SGCB knockout mice share many of the phenotypic deficiencies of LGMD2E patients. To investigate systemic SGCB gene transfer to treat skeletal and cardiac muscle deficits, we designed a self-complementary AAVrh74 vector containing a codon-optimized human SGCB transgene driven by a muscle-specific promoter. We delivered scAAV.MHCK7.hSGCB through the tail vein of SGCB −/− mice to provide a rationale for a clinical trial that would lead to clinically meaningful results. This led to 98.1% transgene expression across all muscles that was accompanied by improvements in histopathology. Serum creatine kinase (CK) levels were reduced following treatment by 85.5%. Diaphragm force production increased by 94.4%, kyphoscoliosis of the spine was significantly reduced by 48.1%, overall ambulation increased by 57%, and vertical rearing increased dramatically by 132% following treatment. Importantly, no adverse effects were seen in muscle of wild-type mice injected systemically with scAAV.hSGCB. In this well-defined model of LGMD2E, we have demonstrated the efficacy and safety of systemic scAAV.hSGCB delivery, and these findings have established a path for clinically beneficial AAV-mediated gene therapy for LGMD2E.
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A revised paradigm currently considers the use of muscle-specific promoters to prevent leaky expression, as well as systemic vector delivery for broader biodistribution via AAV9 and/or AAVrh74, which efficiently target both striated muscle and the CNS.
“To overcome these limitations, a revised paradigm currently considers the use of muscle-specific promoters to prevent leaky expression, as well as systemic vector delivery for broader biodistribution via AAV9 and/or AAVrh74, which efficiently target both striated muscle and the CNS [123-125].”
From Circumventing the packaging limit of AAV-mediated gene replacement therapy for neurological disorders (2022) · cites this paper as [124]
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- Authors
- Pozsgai, E. R., Griffin, D. A., Heller, K. N., Mendell, J. R., & Rodino-Klapac, L. R.
- Affiliations
- Nationwide Children's Hospital (US)
- ORCID
- Mendell, Jerry R.
- Venue
- Molecular Therapy
- Publisher
- Elsevier BV
- Published
- 2017-04
- Volume
- 25
- Issue
- 4
- Pages
- 855-869
- ISSN
- 1525-0016 (ISSN-L)
- PMC
- PMC5383645
- OpenAlex
- W2592994478
- Cited by
- 76
- References
- 51
- Citations by year
- 2026: 3 · 2025: 11 · 2024: 9 · 2023: 14 · 2022: 5 · 2021: 12 · 2020: 12 · 2019: 2 · 2018: 7 · 2017: 1
- FWCI
- 3.99
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Therapy (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Families belonging to the GFB Italian Onlus
- Center for Clinical and Translational Science voucher program at The Ohio State University Wexner Medical Center (UL1TR001070)
- Nationwide Children’s Hospital Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Genetics › Neurogenetic and Muscular Disorders Research
- Keywords
- beta-sarcoglycan, self-complementary AAV, systemic gene therapy, cardiomyopathy, skeletal muscle dystrophy, kyphoscoliosis, creatine kinase, muscle-specific promoter
- MeSH terms
- Dependovirus, Animals, Biopsy, Disease Models, Animal, Genetic Vectors, Humans, Kyphosis, Motor Activity, Cardiomyopathies, Myocardium, Scoliosis, Tissue Distribution, Transduction, Genetic, Gene Transfer Techniques, Mice, Knockout, Muscle, Skeletal, Recovery of Function, Gene Order, Sarcoglycans, Mice, X-Ray Microtomography, Sarcoglycanopathies
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