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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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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Cell-penetrating peptide-conjugated antisense oligonucleotides restore systemic muscle and cardiac dystrophin expression and function

HaiFang Yin1, Hong M. Moulton2, Yiqi Seow1, Corinne Boyd1, Jordan Boutilier2, Patrick Iverson2 and Matthew J.A. Wood1,*

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.


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H. Yin, H. M. Moulton, C. Betts, Y. Seow, J. Boutilier, P. L. Iverson, and M. J.A. Wood
A fusion peptide directs enhanced systemic dystrophin exon skipping and functional restoration in dystrophin-deficient mdx mice
Hum. Mol. Genet., November 15, 2009; 18(22): 4405 - 4414.
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