title: Effective exon skipping and dystrophin restoration by 2'-o-methoxyethyl antisense oligonucleotide in dystrophin-deficient mice.
abstract: Antisense oligonucleotide (AO)-mediated exon-skipping therapy is one of the most promising therapeutic strategies for Duchenne Muscular Dystrophy (DMD) and several AO chemistries have been rigorously investigated. In this report, we focused on the effect of 2'-O-methoxyethyl oligonucleotides (MOE) on exon skipping in cultured mdx myoblasts and mice. Efficient dose-dependent skipping of targeted exon 23 was achieved in myoblasts with MOE AOs of different lengths and backbone chemistries. Furthermore, we established that 25-mer MOE phosphorothioate (PS) AOs provided the greatest exon-skipping efficacy. When compared with 2'O methyl phosphorothioate (2'OmePS) AOs, 25-mer MOE (PS) AOs also showed higher exon-skipping activity in vitro and in mdx mice after intramuscular injections. Characterization of uptake in vitro corroborated with exon-skipping results, suggesting that increased uptake of 25-mer MOE PS AOs might partly contribute to the difference in exon-skipping activity observed in vitro and in mdx mice. Our findings demonstrate the substantial potential for MOE PS AOs as an alternative option for the treatment of DMD.
authors: Research Centre of Basic Medical Science, Tianjin Medical University, Heping District, Tianjin, China.
authors: Lu
authors: L
authors: Yang
authors: Hongjing
authors: H
authors: Niu
authors: Xianjun
authors: X
authors: Gao
authors: Qingsong
authors: Q
authors: Wang
authors: Gang
authors: G
authors: Han
authors: Limin
authors: L
authors: Cao
authors: Chunquan
authors: C
authors: Cai
authors: Jan
authors: J
authors: Weiler
authors: Haifang
authors: H
authors: Yin
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D016189:Dystrophin / Q000235:genetics* / Q000378:metabolism; D005091:Exons; D015316:Genetic Therapy; D006801:Humans; D007273:Injections, Intramuscular; D051379:Mice; D008822:Mice, Transgenic; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D032446:Myoblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D016376:Oligonucleotides, Antisense / Q000235:genetics / Q000494:pharmacology*
chemical_list: D016189:Dystrophin; D016376:Oligonucleotides, Antisense
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