Morpholino oligomer -: Mediated Exon skipping averts the onset of dystrophic pathology in the mdx mouse

被引:121
作者
Fletcher, Sue
Honeyman, Kaite
Fall, Abbie M.
Harding, Penny L.
Johnsen, Russell D.
Steinhaus, Joshua P.
Moulton, Hong M.
Iversen, Patrick L.
Wilton, Stephen D.
机构
[1] Univ Western Australia, Ctr Neuromuscular & Neurol Disorders, Perth, WA 6009, Australia
[2] Univ Western Australia, Royal Perth Hosp, Sch Med & Pharmacol, Cardiovasc Res Grp, Perth, WA 6009, Australia
[3] AVI BioPharma, Corvallis, OR USA
关键词
D O I
10.1038/sj.mt.6300245
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Duchenne and Becker muscular dystrophies are allelic disorders arising from mutations in the dystrophin gene. Duchenne muscular dystrophy is characterized by an absence of functional protein, whereas Becker muscular dystrophy, commonly caused by in-frame deletions, shows synthesis of partially functional protein. Anti-sense oligonucleotides can induce specific exon removal during processing of the dystrophin primary transcript, while maintaining or restoring the reading frame, and thereby overcome protein-truncating mutations. The mdx mouse has a non-sense mutation in exon 23 of the dystrophin gene that precludes functional dystrophin production, and this model has been used in the development of treatment strategies for dystrophinopathies. A phosphorodiamidate morpholino oligomer ( PMO) has previously been shown to exclude exon 23 from the dystrophin gene transcript and induce dystrophin expression in the mdx mouse, in vivo and in vitro. In this report, a cell-penetrating peptide ( CPP)- conjugated oligomer targeted to the mouse dystrophin exon 23 donor splice site was administered to mdx mice by intraperitoneal injection. We demonstrate dystrophin expression and near- normal muscle architecture in all muscles examined, except for cardiac muscle. The CPP greatly enhanced uptake of the PMO, resulting in widespread dystrophin expression.
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收藏
页码:1587 / 1592
页数:6
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