Abstract | BACKGROUND: METHODS: A series of 2'-O-methyl modified oligomers on a phosphorothioate backbone (2OMeAOs) were designed and evaluated for the removal of each exon, and the most effective compounds were then combined to induce dual exon skipping in both myoblast cultures and in vivo. Exon skipping efficiency of 2OMeAOs and phosphorodiamidate morpholino oligomers (PMOs) was evaluated both in vitro and in vivo at the RNA and protein levels. RESULTS: Compared to the original mdx mouse studies, induction of exon skipping from the 4(CV) dystrophin mRNA was far more challenging. PMO cocktails could restore synthesis of near-full length dystrophin protein in cultured 4(CV) myogenic cells and in vivo, after a single intramuscular injection. CONCLUSIONS: By-passing the protein-truncating mutation in the 4(CV) mouse model of muscular dystrophy could not be achieved with single oligomers targeting both exons and was only achieved after the application of AO cocktails to remove exons 52 and 53. As in previous studies, the stability and efficiency of PMOs proved superior to 2OMeAOs for consistent and sustained protein induction in vivo.
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Authors | Chalermchai Mitrpant, Sue Fletcher, Patrick L Iversen, Steve D Wilton |
Journal | The journal of gene medicine
(J Gene Med)
Vol. 11
Issue 1
Pg. 46-56
(Jan 2009)
ISSN: 1521-2254 [Electronic] England |
PMID | 19006096
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | (c) 2008 John Wiley & Sons, Ltd. |
Chemical References |
- Codon, Nonsense
- Dystrophin
- Morpholines
- Morpholinos
- Oligonucleotides, Antisense
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Topics |
- Animals
- Codon, Nonsense
(genetics)
- Dystrophin
(genetics)
- Exons
(genetics)
- Injections, Intramuscular
- Mice
- Mice, Inbred mdx
- Models, Animal
- Morpholines
(administration & dosage, chemistry, therapeutic use)
- Morpholinos
- Muscular Dystrophy, Animal
(drug therapy, genetics)
- Oligonucleotides, Antisense
(administration & dosage, chemistry, therapeutic use)
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