Antisense oligonucleotide-induced exon skipping across the human dystrophin gene transcript
Wilton, S.D., Adams, A.M., Harding, P.L., McClorey, G., Coleman, C. and Fletcher, S. (2007) Antisense oligonucleotide-induced exon skipping across the human dystrophin gene transcript. In: 5th Australasian Gene Therapy Society Meeting, 18 - 20 April 2007, Shine Dome Academy of Science, Canberra.
Antisense oligonucleotides (AOs), directed at amenable splicing motifs across the dystrophin gene transcript, can be used as a potential therapeutic intervention during pre-mRNA splicing. Selected exons are excised using an AO to either remove nonsense mutations or restore the reading frame around frame-shifting mutations in the mature mRNA. In many cases, it should be possible to predict the level of functionality of the induced dystrophin protein by comparing it to similar rearrangements found in Becker muscular dystrophy, a less severe formof Duchenne muscular dystrophy, which arises from in-frame dystrophin deletions. We describe a panel of AOs designed to induce skipping of every exon within the human dystrophin gene transcript, with the exception of the first and last exons. Every exon targeted in vitro was removed from the dystrophin mRNA, although some exons were more efficiently excluded than others. The efficiency with which the targeted exons were excluded could be improved by careful AO design and in some cases combining AOs targeted to a single exon. We have classified the exons according to the ease with which they can be removed from the nascent transcript. No single motif has emerged as a universal AO annealing site for redirection of dystrophin pre-mRNA processing, although the general trend is that the most efficient compounds are directed at motifs in the first half of the target exon.
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