Terminal antisense oligonucleotide modifications can enhance induced exon skipping.
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.
Gebski
Bijanka L
BL
Experimental Molecular Medicine Group, Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Nedlands, Perth 6097, Western Australia.
Errington
Stephen J
SJ
Johnsen
Russell D
RD
Fletcher
Susan
S
Wilton
Stephen D
SD
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D005091:Exons / Q000187:drug effects / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000473:pathology; D009137:Muscular Dystrophy, Animal; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D012322:RNA Precursors / Q000187:drug effects / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D016376:Oligonucleotides, Antisense; D012322:RNA Precursors