Journal article
Large1 gene transfer in older myd mice with severe muscular dystrophy restores muscle function and greatly improves survival
Science advances, Vol.8(21), pp.eabn0379-eabn0379
05/27/2022
DOI: 10.1126/sciadv.abn0379
PMCID: PMC9132445
PMID: 35613260
Abstract
Muscular dystrophy is a progressive and ultimately lethal neuromuscular disease. Although gene editing and gene transfer hold great promise as therapies when administered before the onset of severe clinical symptoms, it is unclear whether these strategies can restore muscle function and improve survival in the late stages of muscular dystrophy.
Large
myd
/Large
myd
(
myd
) mice lack expression of
like-acetylglucosaminyltransferase-1
(
Large1
) and exhibit severe muscle pathophysiology, impaired mobility, and a markedly reduced life span. Here, we show that systemic delivery of AAV2/9 CMV
Large1
(AAV
Large1
) in >34-week-old
myd
mice with advanced disease restores matriglycan expression on dystroglycan, attenuates skeletal muscle pathophysiology, improves motor and respiratory function, and normalizes systemic metabolism, which collectively and markedly extends survival. Our results in a mouse model of muscular dystrophy demonstrate that skeletal muscle function can be restored, illustrating its remarkable plasticity, and that survival can be greatly improved even after the onset of severe muscle pathophysiology.
Large1
gene transfer improves muscle function and extends survival in older mice with severe muscular dystrophy.
Details
- Title: Subtitle
- Large1 gene transfer in older myd mice with severe muscular dystrophy restores muscle function and greatly improves survival
- Creators
- Takahiro Yonekawa - University of IowaAdam J. Rauckhorst - Fraternal Order of EaglesSara El-Hattab - Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center, Department of Molecular Physiology and Biophysics and Department of Neurology, Roy J. and Lucille A. Carver College of Medicine, Howard Hughes Medical Institute, The University of Iowa, Iowa City, IA 52242, USA.Marco A. Cuellar - Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center, Department of Molecular Physiology and Biophysics and Department of Neurology, Roy J. and Lucille A. Carver College of Medicine, Howard Hughes Medical Institute, The University of Iowa, Iowa City, IA 52242, USA.David Venzke - Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center, Department of Molecular Physiology and Biophysics and Department of Neurology, Roy J. and Lucille A. Carver College of Medicine, Howard Hughes Medical Institute, The University of Iowa, Iowa City, IA 52242, USA.Mary E. Anderson - Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center, Department of Molecular Physiology and Biophysics and Department of Neurology, Roy J. and Lucille A. Carver College of Medicine, Howard Hughes Medical Institute, The University of Iowa, Iowa City, IA 52242, USA.Hidehiko Okuma - University of IowaAlvin D. Pewa - University of IowaEric B. Taylor - Fraternal Order of EaglesKevin P. Campbell - Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center, Department of Molecular Physiology and Biophysics and Department of Neurology, Roy J. and Lucille A. Carver College of Medicine, Howard Hughes Medical Institute, The University of Iowa, Iowa City, IA 52242, USA.
- Resource Type
- Journal article
- Publication Details
- Science advances, Vol.8(21), pp.eabn0379-eabn0379
- DOI
- 10.1126/sciadv.abn0379
- PMID
- 35613260
- PMCID
- PMC9132445
- NLM abbreviation
- Sci Adv
- ISSN
- 2375-2548
- eISSN
- 2375-2548
- Language
- English
- Date published
- 05/27/2022
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Iowa Neuroscience Institute; Pharmacy Practice and Science; Fraternal Order of Eagles Diabetes Research Center
- Record Identifier
- 9984297602802771
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