Abstract |
Dystrophin deficiency leads to lethal dilated Duchenne cardiomyopathy. A promising therapy is to deliver a highly abbreviated microdystrophin gene to the heart using adeno-associated virus (AAV). Microdystrophin has been shown to mitigate dystrophin-deficient skeletal muscle disease. However, it is not clear whether microdystrophin is equally effective in treating Duchenne cardiomyopathy. To evaluate microdystrophin therapy in the heart, we injected 5 × 10(12) viral genome particles/mouse of AAV-9 ΔR4-23/ΔC microdystrophin vector via tail vein to ~16-20-month-old (average 18.7-month-old) female mdx mice, a manifesting model of Duchenne cardiomyopathy. Cardiac transduction and heart function were examined at 2-8 months after gene transfer. We observed robust myocardial microdystrophin expression. Electrocardiography (ECG) and left ventricular catheter hemodynamic assays also revealed significant improvement. Furthermore, AAV-microdystrophin therapy prevented dobutamine-stress induced acute cardiac death. We demonstrate for the first time that AAV microdystrophin therapy significantly ameliorates functional deficiency in a phenotypic model of Duchenne cardiomyopathy. Our results support further exploration of microdystrophin therapy to treat Duchenne cardiomyopathy.
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Authors | Brian Bostick, Jin-Hong Shin, Yongping Yue, Dongsheng Duan |
Journal | Molecular therapy : the journal of the American Society of Gene Therapy
(Mol Ther)
Vol. 19
Issue 10
Pg. 1826-32
(Oct 2011)
ISSN: 1525-0024 [Electronic] United States |
PMID | 21811246
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
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Topics |
- Aging
(physiology)
- Animals
- Dependovirus
(genetics)
- Dobutamine
(adverse effects)
- Dystrophin
(genetics, therapeutic use)
- Electrocardiography
- Female
- Genetic Vectors
- Heart Function Tests
- Hemodynamics
- Mice
- Mice, Inbred mdx
- Transduction, Genetic
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