2011 Fiscal Year Final Research Report
Establishment of radical therapy for Fukuyama Muscular Dystrophy
| Project/Area Number |
22790980
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Pediatrics
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| Research Institution | Kobe University (2011)
Osaka University (2010) |
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Principal Investigator |
TANIGUCHI Mariko 神戸大学, 大学院・医学研究科, 特命助教 (00410738)
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| Project Period (FY) |
2010 – 2011
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| Keywords | アンチセンス治療 / 先天性筋ジストロフィー / RNA創薬 / ゲノム創薬 / スプライシング異常 / ドラッグデリバリーシステム |
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| Research Abstract |
Fukuyama muscular dystrophy(FCMD), one of the most common autosomal recessive disorders in Japan, was the first human disease found to result from ancestral insertion of a SINE-VNTR-Alu retrotransposal element(SVA) into a causative gene. Here we show that aberrant mRNA splicing, induced by SVA exon trapping, underlies the molecular pathogenesis of FCMD. Introduction of antisense oligonucleotides(AONs) targeting the splice acceptor, the predicted exonic splicing enhancer, and the intronic splicing enhancer prevented pathogenic exon trapping by SVA in FCMD patient cells and model mice, rescuing normal fukutin mRNA expression and protein production. AON treatment also restored fukutin functions, including as O-glycosylation of.-dystroglycan(.-DG) and laminin binding by.-DG. We have demonstrated the promise of splicing modulation therapy as the first radical clinical treatment for FCMD.
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[Journal Article] Pathogenic exon-trapping by SVA retrotransoposon and rescue in Fukuyama2011
Author(s)
Taniguchi-Ikeda M., Kobayashi K., Kanagawa M., Yu CC., Mori K., Oda T., Kuga A., Kurahashi H., Akman HO., DiMauro S., Kaji R., Yokota T., Takeda S., Toda T.
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Journal Title
muscular dystrophy Nature
Volume: 478
Pages: 127-131
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