Molecular targeting therapy and pathomechanism for Fukuyama muscular dystrophy and related disorders

2013 Fiscal Year Final Research Report

• Project/Area Number: 23249049
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neurology
• Research Institution: Kobe University
• Principal Investigator: TATSUSHI Toda 神戸大学, 医学(系)研究科(研究院), 教授 (30262025)
• Co-Investigator(Renkei-kenkyūsha): KOBAYASHI Kazuhiro 神戸大学, 大学院・医学研究科, 教授 (90324780) ; KANAGAWA Motoi 神戸大学, 大学院・医学研究科, 助教 (00448044) ; IKEDA Mariko (TANIGUCHI Mariko) 神戸大学, 大学院・医学研究科, 特命講師 (00410738)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Keywords: 福山型筋ジストロフィー / レトロトランスポゾン / ジストログリカノパチー / アンチセンス治療 / フクチン / ポストリン酸構造

Research Abstract

Fukuyama muscular dystrophy (FCMD) is the first human disease found to result from ancestral insertion of a SINE-VNTR-Alu (SVA) retrotransposon 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 cells of patients with FCMD and model mice, rescuing normal fukutin mRNA expression and protein production. AON treatment also restored fukutin functions, including O-glycosylation of a-DG and laminin binding by a-DG. Thus, we have discovered in human disease a role for SVA-mediated exon-trapping and demonstrated the promise of splicing modulation therapy as the first radical clinical treatment for FCMD and other SVA-mediated diseases.

Research Products

• [Journal Article] Impaired viability of muscle precursor cells in muscular dystrophy with glycosylation defects and amelioration of its severe phenotype by limited gene expression (2013)
  • Author(s): Kanagawa M, Yu CC, Ito C, Fukada SI, Hozoji-Inada M, Chiyo T, Kuga A, Matsuo M, Sato K, Yamaguchi M, Ito T, Ohtsuka Y, Katanosaka Y, Miyagoe-Suzuki Y, Naruse K, Kobayashi K, Okada T, Takeda S, Toda T
  • Journal Title: Hum Mol Genet Volume: 22 Pages: 3003-3015
  • DOI: 10.1093/hmg/ddt157
  • Peer Reviewed
• [Journal Article] Absence of post-phosphoryl modification in dystroglycanopathy mouse models and wild-type tissues expressing a non-laminin binding form of alpha-dystroglycan (2012)
  • Author(s): Kuga A, Kanagawa M, Sudo A, Chan YM, Tajiri M, Manya H, Kikkawa Y, Nomizu M, Kobayashi K, Endo T, Lu QL, Wada Y, Toda T
  • Journal Title: J Biol Chem Volume: 287 Pages: 9560-9567
  • Peer Reviewed
• [Journal Article] Pathogenic exon-trapping by SVA retrotransposon and rescue in Fukuyama muscular dystrophy (2011)
  • 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
  • Journal Title: Nature Volume: 478 Pages: 127-131
  • DOI: 10.1038/nature10456
  • Peer Reviewed
• [Presentation] Alpha-dystroglycanopathy and molecular targeting therapy (2013)
  • Author(s): Tatsushi Toda
  • Organizer: Third International Workshop for Glycosylation Defects in Muscular Dystrophies
  • Place of Presentation: Omni Charlotte Hotel, Charlotte NC. U.S.A.
  • Year and Date: 2013-04-18
• [Remarks]
  • URL: http://www.med.kobe-u.ac.jp/sinkei/
• [Remarks]
  • URL: http://www.med.kobe-u.ac.jp/clgene/
• [Patent(Industrial Property Rights)] 福山型筋ジストロフィー治療用医薬組成物 (2012)
  • Inventor(s): 戸田達史, 小林千浩, 池田真理子
  • Industrial Property Rights Holder: 国立大学法人神戸大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 特願 2012‐86891
  • Filing Date: 2012-04-05