Nature Medicine9, 1009 - 1014 (2003)
Published online: 6 July 2003; Corrected online: 16 July 2003 | doi:10.1038/nm897
Functional amounts of dystrophin produced by skipping the mutated exon in the mdx dystrophic mouse
Qi Long Lu1, Christopher J Mann2, Fang Lou3, George Bou-Gharios1, Glenn E Morris4, Shao-an Xue5, Sue Fletcher2, Terence A Partridge1
& Stephen D Wilton2
1
Muscle Cell Biology, MRC Clinical Science Centre, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK.
2
Australian Neuromuscular Research Institute, Centre for Neuromuscular and Neurological Disorders, QEII Medical Centre University of Western Australia, Nedlands 6009, Western Australia.
3
University of Hertfordshire, Department of Biosciences, College Lane, Hatfield, Herts, AL10 9AB, UK.
4
MRIC Biochemistry Group, The North East Wales Institute, Plas Coch, Mold Road, Wrexham, LL11 2AW, UK.
5
Department of Immunology, Division of Medicine, Imperial College, Hammersmith Hospital Campus, Du Cane Road, London, W12 0NN, UK.
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.
*NOTE: In the version of this article initially published online, the following errors appeared: The fourth sentence of the abstract was incorrect. It has been changed to, "We have tested this idea in vivo in the mdx dystrophic mouse (carrying a mutation in exon 23 of the dystrophin gene) by combining...to promote skipping of the mutated exon." The sixth sentence of the first paragraph of the Results was incorrect and has been changed. It now reads, "...(C57Bl/10ScSn; designated C57)..." Figure 2 and its legend contained an error. The figure should be labeled with subpanels a and b. The legend should read, "Figure 2 Detection of dystrophin and dystrophin protein complexes. Exon mapping of 2OMeAO-induced dystrophin (a,b) and detection of dystrophin protein complexes (b) in serial sections..." These mistakes have been
corrected for the HTML and print versions of the article.
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated
