Document Detail


Microdystrophin ameliorates muscular dystrophy in the canine model of duchenne muscular dystrophy.
MedLine Citation:
PMID:  23319056     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Dystrophin deficiency results in lethal Duchenne muscular dystrophy (DMD). Substituting missing dystrophin with abbreviated microdystrophin has dramatically alleviated disease in mouse DMD models. Unfortunately, translation of microdystrophin therapy has been unsuccessful in dystrophic dogs, the only large mammalian model. Approximately 70% of the dystrophin-coding sequence is removed in microdystrophin. Intriguingly, loss of ≥50% dystrophin frequently results in severe disease in patients. To test whether the small gene size constitutes a fundamental design error for large mammalian muscle, we performed a comprehensive study using 22 dogs (8 normal and 14 dystrophic). We delivered the ΔR2-15/ΔR18-19/ΔR20-23/ΔC microdystrophin gene to eight extensor carpi ulnaris (ECU) muscles in six dystrophic dogs using Y713F tyrosine mutant adeno-associated virus (AAV)-9 (2.6 × 10(13) viral genome (vg) particles/muscle). Robust expression was observed 2 months later despite T-cell infiltration. Major components of the dystrophin-associated glycoprotein complex (DGC) were restored by microdystrophin. Treated muscle showed less inflammation, fibrosis, and calcification. Importantly, therapy significantly preserved muscle force under the stress of repeated cycles of eccentric contraction. Our results have established the proof-of-concept for microdystrophin therapy in dystrophic muscles of large mammals and set the stage for clinical trial in human patients.
Authors:
Jin-Hong Shin; Xiufang Pan; Chady H Hakim; Hsiao T Yang; Yongping Yue; Keqing Zhang; Ronald L Terjung; Dongsheng Duan
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-01-15
Journal Detail:
Title:  Molecular therapy : the journal of the American Society of Gene Therapy     Volume:  21     ISSN:  1525-0024     ISO Abbreviation:  Mol. Ther.     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-04-01     Completed Date:  2013-11-01     Revised Date:  2014-04-01    
Medline Journal Info:
Nlm Unique ID:  100890581     Medline TA:  Mol Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  750-7     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Blotting, Western
Dogs
Dystrophin / genetics,  metabolism*
Gene Transfer Techniques
Male
Mice
Muscular Dystrophy, Animal / metabolism,  therapy*
Muscular Dystrophy, Duchenne / metabolism,  therapy*
Grant Support
ID/Acronym/Agency:
AR-49419/AR/NIAMS NIH HHS; HL-91883/HL/NHLBI NIH HHS; R01 AR049419/AR/NIAMS NIH HHS; R01 HL091883/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Dystrophin
Comments/Corrections

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