Human Molecular Genetics Advance Access originally published online on September 10, 2008
Human Molecular Genetics 2008 17(24):3909-3918; doi:10.1093/hmg/ddn293
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Cell-penetrating peptide-conjugated antisense oligonucleotides restore systemic muscle and cardiac dystrophin expression and function
1 Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK 2 AVI Biopharma Inc., Corvallis, OR, USA
* To whom correspondence should be addressed. Tel: +44 1865272419; Fax: +44 1865272420; Email: matthew.wood{at}dpag.ox.ac.uk
Received June 30, 2008; Accepted September 9, 2008
Antisense oligonucleotides (AOs) have the potential to induce functional dystrophin protein expression via exon skipping by restoring in-frame transcripts in the majority of patients suffering from Duchenne muscular dystrophy (DMD). AOs of morpholino phosphoroamidate (PMO) and 2'-O-methyl phosphorothioate RNA (2'Ome RNA) chemistry have been shown to restore dystrophin expression in skeletal muscle but not in heart, following high-dose systemic delivery in murine models of muscular dystrophy (mdx). Exploiting the cell transduction properties of two basic arginine-rich cell penetrating peptides, we demonstrate widespread systemic correction of dystrophin expression in body-wide muscles and cardiac tissue in adult dystrophic mdx mice, with a single low-dose injection of peptide-conjugated PMO AO. This approach was sufficient to restore uniform, high-level dystrophin protein expression in peripheral muscle and cardiac tissue, with robust sarcolemmal relocalization of the dystrophin-associated protein complex and functional improvement in muscle. Peptide-conjugated AOs therefore have significant potential for systemic correction of the DMD phenotype.