Cell-penetrating peptide-conjugated antisense oligonucleotides restore systemic muscle and cardiac dystrophin expression and function.
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.
Yin
HaiFang
H
Department of Physiology, Anatomy and Genetics, University of Oxford, South Parks Road, Oxford OX1 3QX, UK.
Moulton
Hong M
HM
Seow
Yiqi
Y
Boyd
Corinne
C
Boutilier
Jordan
J
Iverson
Patrick
P
Wood
Matthew J A
MJ
D000818:Animals; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000235:genetics*; D004305:Dose-Response Relationship, Drug; D016189:Dystrophin / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006335:Heart Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D009025:Morpholines / Q000493:pharmacokinetics / Q000627:therapeutic use; D060172:Morpholinos; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D009137:Muscular Dystrophy, Animal / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000737:chemistry / Q000235:genetics* / Q000493:pharmacokinetics; D010455:Peptides / Q000235:genetics / Q000493:pharmacokinetics / Q000627:therapeutic use*
D016189:Dystrophin; D009025:Morpholines; D060172:Morpholinos; D016376:Oligonucleotides, Antisense; D010455:Peptides
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