Morpholino Oligomer–mediated exon skipping averts the onset of dystrophic pathology in the mdx mouse

S. Fletcher; K. Honeyman; A.M. Fall; P.L. Harding; R.D. Johnsen; J.P. Steinhaus; H.M. Moulton; P.L. Iversen; S.D. Wilton

doi:10.1038/sj.mt.6300245

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Morpholino Oligomer–mediated exon skipping averts the onset of dystrophic pathology in the mdx mouse

Journal article

Peer reviewed

Morpholino Oligomer–mediated exon skipping averts the onset of dystrophic pathology in the mdx mouse

S. Fletcher, K. Honeyman, A.M. Fall, P.L. Harding, R.D. Johnsen, J.P. Steinhaus, H.M. Moulton, P.L. Iversen and S.D. Wilton

Molecular Therapy, Vol.15(9), pp.1587-1592

2007

DOI: https://doi.org/10.1038/sj.mt.6300245

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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.

Details

Title: Morpholino Oligomer–mediated exon skipping averts the onset of dystrophic pathology in the mdx mouse
Authors/Creators: S. Fletcher (Author/Creator) - The University of Western Australia
K. Honeyman (Author/Creator) - The University of Western Australia
A.M. Fall (Author/Creator) - The University of Western Australia
P.L. Harding (Author/Creator) - The University of Western Australia
R.D. Johnsen (Author/Creator) - The University of Western Australia
J.P. Steinhaus (Author/Creator) - The University of Western Australia
H.M. Moulton (Author/Creator) - Sarepta Therapeutics (United States)
P.L. Iversen (Author/Creator) - Sarepta Therapeutics (United States)
S.D. Wilton (Author/Creator) - The University of Western Australia
Publication Details: Molecular Therapy, Vol.15(9), pp.1587-1592
Publisher: Nature Publishing Group
Identifiers: 991005543596407891
Copyright: 2007 The American Society of Gene Therapy
Murdoch Affiliation: Murdoch University
Language: English
Resource Type: Journal article

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Collaboration types: Industry collaboration; Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.255 Musculoskeletal Disorders; 1.255.628 Duchenne Muscular Dystrophy
Web Of Science research areas: Biotechnology & Applied Microbiology; Genetics & Heredity; Medicine, Research & Experimental
ESI research areas: Clinical Medicine