Functional amounts of dystrophin produced by skipping the mutated exon in the mdx dystrophic mouse

Q.L. Lu; C.J. Mann; F. Lou; G. Bou-Gharios; G.E. Morris; S-A Xue; S. Fletcher; T.A. Partridge; S.D. Wilton

doi:10.1038/nm897

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Functional amounts of dystrophin produced by skipping the mutated exon in the mdx dystrophic mouse

Journal article

Peer reviewed

Functional amounts of dystrophin produced by skipping the mutated exon in the mdx dystrophic mouse

Q.L. Lu, C.J. Mann, F. Lou, G. Bou-Gharios, G.E. Morris, S-A Xue, S. Fletcher, T.A. Partridge and S.D. Wilton

Nature Medicine, Vol.9(8), pp.1009-1014

2003

DOI: https://doi.org/10.1038/nm897

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Abstract

As a target for gene therapy, Duchenne muscular dystrophy (DMD) presents many obstacles but also an unparalleled prospect for correction by alternative splicing. The majority of mutations in the dystrophin gene occur in the region encoding the spectrin-like central rod domain, which is largely dispensable. Thus, splicing around mutations can generate a shortened but in-frame transcript, permitting translation of a partially functional dystrophin protein. We have tested this idea in vivo in the mdx dystrophic mouse (carrying a mutation in exon 23 of the dystrophin gene) by combining a potent transfection protocol with a 2-O-methylated phosphorothioated antisense oligoribonucleotide (2OMeAO) designed to promote skipping of the mutated exon*. The treated mice show persistent production of dystrophin at normal levels in large numbers of muscle fibers and show functional improvement of the treated muscle. Repeated administration enhances dystrophin expression without eliciting immune responses. Our data establishes the realistic practicality of an approach that is applicable, in principle, to a majority of cases of severe dystrophinopathy.

Details

Title: Functional amounts of dystrophin produced by skipping the mutated exon in the mdx dystrophic mouse
Authors/Creators: Q.L. Lu (Author/Creator) - Hammersmith Hospital
C.J. Mann (Author/Creator) - The University of Western Australia
F. Lou (Author/Creator) - University of Hertfordshire
G. Bou-Gharios (Author/Creator) - Hammersmith Hospital
G.E. Morris (Author/Creator) - MRIC Biochemistry Group, The North East Wales Institute, Plas Coch, Wrexham, UK
S-A Xue (Author/Creator) - Hammersmith Hospital
S. Fletcher (Author/Creator) - The University of Western Australia
T.A. Partridge (Author/Creator) - Hammersmith Hospital
S.D. Wilton (Author/Creator) - The University of Western Australia
Publication Details: Nature Medicine, Vol.9(8), pp.1009-1014
Publisher: Nature Publishing Group
Identifiers: 991005543540407891
Copyright: 2003 Nature Publishing Group
Murdoch Affiliation: Murdoch University
Language: English
Resource Type: Journal article

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Collaboration types: 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: Biochemistry & Molecular Biology; Cell Biology; Medicine, Research & Experimental
ESI research areas: Molecular Biology & Genetics