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Functional amounts of dystrophin produced by skipping the mutated exon in the mdx dystrophic mouse.
Nat Med. 2003 Aug; 9(8):1009-14.NMed

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.

Authors+Show Affiliations

Muscle Cell Biology, MRC Clinical Science Centre, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK. qi.long-lu@csc.mrc.ac.ukNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

12847521

Citation

Lu, Qi Long, et al. "Functional Amounts of Dystrophin Produced By Skipping the Mutated Exon in the Mdx Dystrophic Mouse." Nature Medicine, vol. 9, no. 8, 2003, pp. 1009-14.
Lu QL, Mann CJ, Lou F, et al. Functional amounts of dystrophin produced by skipping the mutated exon in the mdx dystrophic mouse. Nat Med. 2003;9(8):1009-14.
Lu, Q. L., Mann, C. J., Lou, F., Bou-Gharios, G., Morris, G. E., Xue, S. A., Fletcher, S., Partridge, T. A., & Wilton, S. D. (2003). Functional amounts of dystrophin produced by skipping the mutated exon in the mdx dystrophic mouse. Nature Medicine, 9(8), 1009-14.
Lu QL, et al. Functional Amounts of Dystrophin Produced By Skipping the Mutated Exon in the Mdx Dystrophic Mouse. Nat Med. 2003;9(8):1009-14. PubMed PMID: 12847521.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Functional amounts of dystrophin produced by skipping the mutated exon in the mdx dystrophic mouse. AU - Lu,Qi Long, AU - Mann,Christopher J, AU - Lou,Fang, AU - Bou-Gharios,George, AU - Morris,Glenn E, AU - Xue,Shao-an, AU - Fletcher,Sue, AU - Partridge,Terence A, AU - Wilton,Stephen D, Y1 - 2003/07/06/ PY - 2003/04/11/received PY - 2003/06/10/accepted PY - 2003/7/9/pubmed PY - 2003/10/1/medline PY - 2003/7/9/entrez SP - 1009 EP - 14 JF - Nature medicine JO - Nat Med VL - 9 IS - 8 N2 - 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. SN - 1078-8956 UR - https://www.unboundmedicine.com/medline/citation/12847521/Functional_amounts_of_dystrophin_produced_by_skipping_the_mutated_exon_in_the_mdx_dystrophic_mouse_ L2 - https://doi.org/10.1038/nm897 DB - PRIME DP - Unbound Medicine ER -