Amelioration of laminin-α2-deficient congenital muscular dystrophy by somatic gene transfer of miniagrin
Open accessAbstract
Congenital muscular dystrophy (CMD) is characterized by severe muscle wasting, premature death in early childhood, and lack of effective treatment. Most of the CMD cases are caused by genetic mutations of laminin-α2, which is essential for the structural integrity of muscle extracellular matrix. Here, we report that somatic gene delivery of a structurally unrelated protein, a miniature version of agrin, functionally compensates for laminin-α2 deficiency in the murine models of CMD. Adeno-associated virus-mediated overexpression of miniagrin restored the structural integrity of myofiber basal lamina, inhibited interstitial fibrosis, and ameliorated dystrophic pathology. Furthermore, systemic gene delivery of miniagrin into multiple vital muscles significantly improved whole body growth and motility and quadrupled the lifespan (50% survival) of the dystrophic mice. Thus, our study demonstrated the efficacy of somatic gene therapy in a mouse model of CMD.
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In 2005, the Xiao lab showed that systemic delivery of AAV1/2-miniagrin vectors into different muscles of an MDC1A-mouse model quadrupled its lifespan, improving whole-body growth and motility.
“In 2005, the Xiao lab showed that systemic delivery of AAV1/2-miniagrin vectors into different muscles of an MDC1A-mouse model quadrupled its lifespan, improving whole-body growth and motility [116].”
From Circumventing the packaging limit of AAV-mediated gene replacement therapy for neurological disorders (2022) · cites this paper as [116]
Cites
Gene therapy vectors based on adeno-associated virus type 1
Xiao, W., Chirmule, N., Berta, S. C., McCullough, B., Gao, G., & Wilson, J. M. (1999) · Journal of Virology · doi:10.1128/jvi.73.5.3994-4003.1999 · Cited by 541 · see citing works
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Qiao, C., Yuan, Z., Li, J., He, B., Zheng, H., Mayer, C., Li, J., & Xiao, X. (2011) · Gene Therapy · doi:10.1038/gt.2010.157 · Cited by 163 · see citing works
Self-citationProteasome inhibition improves the muscle of laminin α2 chain-deficient mice.
Carmignac, V., Quéré, R., & Durbeej, M. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddq499 · Cited by 58 · see citing works
Marrone, L., Marchi, P. M., & Azzouz, M. (2022) · Expert Opinion on Biological Therapy · doi:10.1080/14712598.2022.2012148 · Cited by 56 · see citing works
“agrin vectors into different muscles of an MDC1A-mouse model quadrupled its lifespan, improving whole-body growth and motility [116].”
Background
- Authors
- Qiao, C., Li, J., Zhu, T., Draviam, R., Watkins, S., Ye, X., Chen, C., Li, J., & Xiao, X.
- Affiliations
- University of Pittsburgh (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2005-08-15
- Volume
- 102
- Issue
- 34
- Pages
- 11999-12004
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC1189311
- OpenAlex
- W2090667030
- Cited by
- 92
- References
- 1
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 2 · 2022: 2 · 2021: 2 · 2020: 3 · 2019: 2 · 2018: 8 · 2017: 9 · 2016: 1 · 2015: 5 · 2014: 1 · 2013: 2 · 2012: 3
- FWCI
- 3.95
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Muscular Dystrophy Association
- National Institutes of Health (5u54ar050733-06)
- National Institute of Neurological Disorders and Stroke (NS 46546, U01NS046546)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR50733, U54-AR050733)
- 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
- congenital muscular dystrophy, agrin, somatic gene transfer, adeno-associated virus, basement membrane, interstitial fibrosis, dystrophic mice, lifespan extension, gene therapy
- MeSH terms
- Dependovirus, Animals, Base Sequence, Basement Membrane, Fluorescent Antibody Technique, Genetic Vectors, Laminin, Locomotion, Longevity, Molecular Sequence Data, Muscular Dystrophies, Genetic Therapy, Gene Expression, Sequence Analysis, DNA, DNA Primers, Gene Transfer Techniques, Agrin, Mice, Knockout, Muscle, Skeletal, Reverse Transcriptase Polymerase Chain Reaction, Protein Sorting Signals, Mice
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