Targeted exon skipping to address “Leaky” mutations in the dystrophin gene

S. Fletcher; C.F. Adkin; P. Meloni; B. Wong; F. Muntoni; R. Kole; C. Fragall; K. Greer; R. Johnsen; S.D. Wilton

doi:10.1038/mtna.2012.40

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Targeted exon skipping to address “Leaky” mutations in the dystrophin gene

Journal article

Open access

Peer reviewed

Targeted exon skipping to address “Leaky” mutations in the dystrophin gene

S. Fletcher, C.F. Adkin, P. Meloni, B. Wong, F. Muntoni, R. Kole, C. Fragall, K. Greer, R. Johnsen and S.D. Wilton

Molecular Therapy — Nucleic Acids, Vol.1(10), e48

2012

DOI: https://doi.org/10.1038/mtna.2012.40

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Abstract

Protein-truncating mutations in the dystrophin gene lead to the progressive muscle wasting disorder Duchenne muscular dystrophy, whereas in-frame deletions typically manifest as the milder allelic condition, Becker muscular dystrophy. Antisense oligomer-induced exon skipping can modify dystrophin gene expression so that a disease-associated dystrophin pre-mRNA is processed into a Becker muscular dystrophy-like mature transcript. Despite genomic deletions that may encompass hundreds of kilobases of the gene, some dystrophin mutations appear “leaky”, and low levels of high molecular weight, and presumably semi-functional, dystrophin are produced. A likely causative mechanism is endogenous exon skipping, and Duchenne individuals with higher baseline levels of dystrophin may respond more efficiently to the administration of splice-switching antisense oligomers. We optimized excision of exons 8 and 9 in normal human myoblasts, and evaluated several oligomers in cells from eight Duchenne muscular dystrophy patients with deletions in a known “leaky” region of the dystrophin gene. Inter-patient variation in response to antisense oligomer induced skipping in vitro appeared minimal. We describe oligomers targeting exon 8, that unequivocally increase dystrophin above baseline in vitro, and propose that patients with leaky mutations are ideally suited for participation in antisense oligomer mediated splice-switching clinical studies.

Details

Title: Targeted exon skipping to address “Leaky” mutations in the dystrophin gene
Authors/Creators: S. Fletcher (Author/Creator) - The University of Western Australia
C.F. Adkin (Author/Creator) - The University of Western Australia
P. Meloni (Author/Creator) - The University of Western Australia
B. Wong (Author/Creator) - Cincinnati Children's Hospital Medical Center
F. Muntoni (Author/Creator) - University College London
R. Kole (Author/Creator) - Sarepta Therapeutics (United States)
C. Fragall (Author/Creator) - The University of Western Australia
K. Greer (Author/Creator) - The University of Western Australia
R. Johnsen (Author/Creator) - The University of Western Australia
S.D. Wilton (Author/Creator) - The University of Western Australia
Publication Details: Molecular Therapy — Nucleic Acids, Vol.1(10), e48
Publisher: Nature Publishing Group
Identifiers: 991005540088007891
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: Medicine, Research & Experimental
ESI research areas: Biology & Biochemistry