Terminal antisense oligonucleotide modifications can enhance induced exon skipping

B.L. Gebski, S.J. Errington, R.D. Johnson, Susan Fletcher, Steve Wilton

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)


Induction of specific exon skipping during the processing of the dystrophin gene transcript is being pursued as a potential therapy for Duchenne muscular dystrophy. Antisense oligonucleotides directed at motifs involved in pre-mRNA processing can manipulate dystrophin exon incorporation in the mature gene transcript. We have compared the exon skipping ability of oligodeoxyribonucleotides with compounds of the identical sequence incorporating 2'-O-methyl modified bases. Antisense oligonucleotides composed entirely of 2'-O-methyl modified bases on a phosphorothioate backbone were consistently more efficient at inducing exon skipping than comparable oligodeoxyribonucleotides. Chimeric antisense oligonucleotides, mixtures of unmodified and 2'-O-methyl modified bases, induced intermediate levels of exon skipping. In addition, we describe terminal modifications that may be incorporated into the 2'-O-methyl antisense oligonucleotides to further enhance efficiency of exon skipping. Our findings suggest that 2'-O-methyl antisense oligonucleotides should be considered for human clinical trials involving targeted exon skipping in dystrophin gene expression in preference to oligodeoxyribonucleotides. (c) 2005 Elsevier B.V. All rights reserved.
Original languageEnglish
Pages (from-to)622-629
JournalNeuromuscular Disorders
Issue number9-10
Publication statusPublished - 2005


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