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

TitleCell-penetrating peptide-conjugated antisense oligonucleotides restore systemic muscle and cardiac dystrophin expression and function.
Publication TypeJournal Article
Year of Publication2008
AuthorsYin H, Moulton HM, Seow Y, Boyd C, Boutilier J, Iverson P, Wood MJA
JournalHuman molecular genetics
Volume17
Issue24
Pagination3909-18
Date Published2008 Dec 15
ISSN1460-2083
KeywordsAnimals, 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
Abstract

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.

DOI10.1093/hmg/ddn293
Alternate JournalHum. Mol. Genet.