%0 Journal Article
%T Mismatched single stranded antisense oligonucleotides can induce efficient dystrophin splice switching
%A Clayton T Fragall
%A Abbie M Adams
%A Russell D Johnsen
%A Ryszard Kole
%A Sue Fletcher
%A Steve D Wilton
%J BMC Medical Genetics
%D 2011
%I BioMed Central
%R 10.1186/1471-2350-12-141
%X Here we report preclinical testing of a panel of splice switching antisense oligomers, designed to excise exon 25 from the dystrophin transcript, in normal and dystrophic patient cells. These patient cells harbour a single base insertion in exon 25 that lies within the target sequence of an oligomer shown to be effective at removing exon 25.It was anticipated that such a mutation would compromise oligomer binding and efficiency. However, we show that, despite the mismatch an oligomer, designed and optimised to excise exon 25 from the normal dystrophin mRNA, removes the mutated exon 25 more efficiently than the mutation-specific oligomer.This raises the possibility that mismatched AOs could still be therapeutically applicable in some cases, negating the necessity to produce patient-specific compounds.Antisense oligomer (AO) induced exon skipping has emerged as a promising approach to reduce the severity of Duchenne Muscular Dystrophy (DMD), progressing rapidly from concept to the completion of several clinical trials [1-4]. This therapy uses AOs to modify splicing during pre-RNA processing, such that a DMD-associated exon is removed and a shorter but partially functional Becker muscular dystrophy (BMD)-like dystrophin isoform is produced. Most commonly, splice switching AOs are designed to target motifs in the normal dystrophin gene transcript, which is appropriate, since the most common type of DMD mutation is a deletion of one or more exons and it is the normal exon, flanking the deletion that must be removed to restore the reading frame. In addition, it may be assumed that normal exons will generally be more difficult to dislodge than a mutated counter-part, since the full complement of splicing motifs will be present in the former.Disease-causing gene lesions, silent polymorphisms or small intra-exonic deletions, insertions or substitutions may occur within the oligomer annealing region, or impact upon splice control motifs. These could potentially alter the effi
%U http://www.biomedcentral.com/1471-2350/12/141