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Human Molecular Genetics Advance Access published online on September 10, 2008
Human Molecular Genetics, 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 JA Wood1,*

1 Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, OX1 3QX, UK 2 AVI Biopharma Inc., Corvallis, Oregon, USA

* Correspondence Should be addressed to Dr Matthew JA Wood: Department of Physiology, Anatomy and Genetics, University of Oxford South Parks Road, Oxford, OX1 3QX, UK matthew.wood{at}dpag.ox.ac.uk Tel: + 44 (0)1865 272419 Fax: +44 (0)1865 272420

Received June 30, 2008; Revised September 5, 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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