Cardiovascular Research Advance Access first published online on October 8, 2009
This version [Corrected Proof] published online on November 3, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp335
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Long-term improvement in mdx cardiomyopathy after therapy with peptide-conjugated morpholino oligomers
1 Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
2 Thalassemia Research Center and Institute of Molecular Biology and Genetics, Mahidol University, Bangkok, Thailand
3 AVI BioPharma, Inc., Corvallis, OR, USA
4 McAllister Heart Institute, University of North Carolina, 8200 Medical Biomolecular Research Bldg., 103 Mason Farm Road, Chapel Hill, NC, USA
5 Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA
* Corresponding author. Tel: +1 919 843 1938, Fax: +1 919 843 4585, Email: monte_willis{at}med.unc.edu
Aims: The cardiomyopathy found in Duchenne muscular dystrophy (DMD) is responsible for death due to heart failure in 
30% of patients and additionally contributes to many DMD morbidities. Strategies to bypass DMD-causing mutations to allow an increase in body-wide dystrophin have proved promising, but increasing cardiac dystrophin continues to be challenging. The purpose of this study was to determine if therapeutic restoration of cardiac dystrophin improved the significant cardiac hypertrophy and diastolic dysfunction identified in X-linked muscular dystrophy (mdx) dystrophin-null mouse due to a truncation mutation over time after treatment.
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.
KEYWORDS Duchenne muscular dystrophy; Morpholino; Oligomers; Cardiomyopathy; Therapy; Exon skipping; Alternative RNA splicing
Time for primary review: 23 days
All work performed at the University of North Carolina-Chapel Hill.