Abstract | AIMS: METHODS AND RESULTS: Mice lacking dystrophin due to a truncation mutation (mdx) were given an arginine-rich, cell-penetrating, peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO) that delivered a splice-switching oligonucleotide-mediated exon skipping therapy to restore dystrophin in mdx mice before the development of detectable cardiomyopathy. PPMO successfully restored cardiac dystrophin expression, preserved cardiac sarcolemma integrity, and prevented the development of cardiac pathology that develops in mdx-null mice over time. By echocardiography and Doppler analysis of the mitral valve, we identified that PPMO treatment of mdx mice prevented the cardiac hypertrophy and diastolic dysfunction identified in sham-treated, age-matched mdx mice, characteristic of DMD patients early in the disease process, in as little as 5-6 weeks after the initiation of treatment. Surprisingly, despite the short-term replacement of cardiac dystrophin (<1% present after 12 weeks by immunodetection), PPMO therapy also provided a durable cardiac improvement in cardiac hypertrophy and diastolic dysfunction for up to 7 months after the initiation of treatment. CONCLUSION: These results demonstrate for the first time that PPMO-mediated exon skipping therapy early in the course of DMD may effectively prevent or slow down associated cardiac hypertrophy and diastolic dysfunction with significant long-term impact.
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Authors | Natee Jearawiriyapaisarn, Hong M Moulton, Peter Sazani, Ryszard Kole, Monte S Willis |
Journal | Cardiovascular research
(Cardiovasc Res)
Vol. 85
Issue 3
Pg. 444-53
(Feb 01 2010)
ISSN: 1755-3245 [Electronic] England |
PMID | 19815563
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Dystrophin
- Morpholines
- Morpholinos
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Topics |
- Animals
- Cardiomegaly
(prevention & control)
- Cardiomyopathies
(therapy)
- Diastole
- Dystrophin
(genetics)
- Genetic Therapy
(methods)
- Mice
- Mice, Inbred C57BL
- Mice, Inbred mdx
- Morpholines
(administration & dosage)
- Morpholinos
- Muscular Dystrophy, Duchenne
(complications, genetics, therapy)
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