Targeted exon skipping as a potential gene correction therapy for Duchenne muscular dystrophy

Abstract

Duchenne muscular dystrophy is primarily caused by frame-disrupting mutations in the Duchenne muscular dystrophy gene which abort dystrophin synthesis. We have explored a gene correction therapy aimed at restoration of the reading frame in Duchenne muscular dystrophy patients. Through the binding of antisense oligoribonucleotides to exon-internal sequences in the pre-mRNA, the splicing can be manipulated in such a manner that the targeted exon is skipped and a slightly shorter, but in-frame, transcript is generated. We recently showed that antisense oligoribonucleotide-mediated skipping of exon 46 efficiently induced dystrophin synthesis in cultured muscle cells from Duchenne muscular dystrophy patients carrying an exon 45 deletion. In this study we have identified antisense oligoribonucleotides with which the skipping of 11 other Duchenne muscular dystrophy exons could be induced in cultured human muscle cells. The targeted skipping of only one particular exon may restore the reading frame in a series of patients with different mutations. Accordingly, these antisense oligoribonucleotides would allow correction of over 50% of deletions and 22% of duplications reported in the Leiden DMD-mutation Database.