Morpholino oligomer-mediated exon skipping averts the onset of dystrophic pathology in the mdx mouse.

TitleMorpholino oligomer-mediated exon skipping averts the onset of dystrophic pathology in the mdx mouse.
Publication TypeJournal Article
Year of Publication2007
AuthorsFletcher S, Honeyman K, Fall AM, Harding PL, Johnsen RD, Steinhaus JP, Moulton HM, Iversen PL, Wilton SD
JournalMolecular therapy : the journal of the American Society of Gene Therapy
Volume15
Issue9
Pagination1587-92
Date Published2007 Sep
ISSN1525-0016
KeywordsAnimals, Dystrophin, Exons, Gene Expression, Genetic Therapy, Injections, Intraperitoneal, Mice, Mice, Inbred mdx, Morpholines, Morpholinos, Muscles, Muscular Dystrophy, Duchenne, Mutation, Oligonucleotides, Antisense, Reverse Transcriptase Polymerase Chain Reaction
Abstract

Duchenne and Becker muscular dystrophies are allelic disorders arising from mutations in the dystrophin gene. Duchenne muscular dystrophy is characterized by an absence of functional protein, whereas Becker muscular dystrophy, commonly caused by in-frame deletions, shows synthesis of partially functional protein. Anti-sense oligonucleotides can induce specific exon removal during processing of the dystrophin primary transcript, while maintaining or restoring the reading frame, and thereby overcome protein-truncating mutations. The mdx mouse has a non-sense mutation in exon 23 of the dystrophin gene that precludes functional dystrophin production, and this model has been used in the development of treatment strategies for dystrophinopathies. A phosphorodiamidate morpholino oligomer (PMO) has previously been shown to exclude exon 23 from the dystrophin gene transcript and induce dystrophin expression in the mdxmouse, in vivo and in vitro. In this report, a cell-penetrating peptide (CPP)-conjugated oligomer targeted to the mouse dystrophin exon 23 donor splice site was administered to mdxmice by intraperitoneal injection. We demonstrate dystrophin expression and near-normal muscle architecture in all muscles examined, except for cardiac muscle. The CPP greatly enhanced uptake of the PMO, resulting in widespread dystrophin expression.

DOI10.1038/sj.mt.6300245
Alternate JournalMol. Ther.