Document Detail

Adeno-associated viral-mediated LARGE gene therapy rescues the muscular dystrophic phenotype in mouse models of dystroglycanopathy.
MedLine Citation:
PMID:  23379513     Owner:  NLM     Status:  MEDLINE    
Dystroglycanopathies are a group of congenital muscular dystrophies (CMD) often caused by mutations in genes encoding glycosyltransferases that lead to hypoglycosylation of α-dystroglycan (α-DG) and reduce its extracellular matrix-binding activity. Overexpressing LARGE (formerly known as like-glycosyltransferase) generates an extracellular matrix-binding carbohydrate epitope in cells with CMD-causing mutations in not only LARGE but also other glycosyltransferases, including POMT1, POMGnT1, and fukutin, creating the possibilities of a one-for-all gene therapy. To determine the feasibility of LARGE gene therapy, a serotype 9 adeno-associated viral vector for overexpressing LARGE (AAV9-LARGE) was injected intracardially into newborns of two mouse models of CMD: the natural LARGE mutant Large(myd) mice and protein O-mannose N-acetylglucosaminyltransferase 1 (POMGnT1) knockout mice. AAV9-LARGE virus treatment yielded partial restoration of α-DG glycosylation and ligand-binding activity. The muscular dystrophy phenotype in skeletal muscles was ameliorated as revealed by significantly reduced fibrosis, necrosis, and numbers of centrally located nuclei with improved motor function. These results indicate that LARGE overexpression in vivo by AAV9-mediated gene therapy is effective at restoring functional glycosylation of α-DG and rescuing the muscular dystrophy phenotype in deficiency of not only LARGE but also POMGnT1, providing evidence that in vivo LARGE gene therapy may be broadly useful in dystroglycanopathies.
Miao Yu; Yonglin He; Kejian Wang; Peng Zhang; Shengle Zhang; Huaiyu Hu
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Human gene therapy     Volume:  24     ISSN:  1557-7422     ISO Abbreviation:  Hum. Gene Ther.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-03-21     Completed Date:  2013-09-06     Revised Date:  2014-03-06    
Medline Journal Info:
Nlm Unique ID:  9008950     Medline TA:  Hum Gene Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  317-30     Citation Subset:  IM    
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MeSH Terms
Dependovirus / genetics*
Disease Models, Animal
Dystroglycans / metabolism
Fibrosis / genetics,  prevention & control
Genetic Therapy*
Genetic Vectors / administration & dosage,  genetics*
Mice, Transgenic
Motor Activity
Muscle, Skeletal / metabolism,  pathology
Muscular Dystrophies / genetics*,  therapy*
N-Acetylglucosaminyltransferases / genetics*
Transduction, Genetic
Grant Support
Reg. No./Substance:
146888-27-9/Dystroglycans; EC 2.4.1.-/Large protein, mouse; EC 2.4.1.-/N-Acetylglucosaminyltransferases

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