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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.

Original publication

DOI

10.1093/hmg/ddn293

Type

Journal article

Journal

Hum Mol Genet

Publication Date

15/12/2008

Volume

17

Pages

3909 - 3918

Keywords

Animals, Cell Membrane Permeability, Dose-Response Relationship, Drug, Dystrophin, Gene Expression Regulation, Heart Injuries, Mice, Mice, Inbred C57BL, Mice, Inbred mdx, Morpholines, Morpholinos, Muscle, Skeletal, Muscular Dystrophy, Animal, Oligonucleotides, Antisense, Peptides