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.