論文

査読有り
2017年5月

Development of an orally available inhibitor of CLK1 for skipping a mutated dystrophin exon in Duchenne muscular dystrophy

SCIENTIFIC REPORTS
  • Yukiya Sako
  • ,
  • Kensuke Ninomiya
  • ,
  • Yukiko Okuno
  • ,
  • Masayasu Toyomoto
  • ,
  • Atsushi Nishida
  • ,
  • Yuka Koike
  • ,
  • Kenji Ohe
  • ,
  • Isao Kii
  • ,
  • Suguru Yoshida
  • ,
  • Naohiro Hashimoto
  • ,
  • Takamitsu Hosoya
  • ,
  • Masafumi Matsuo
  • ,
  • Masatoshi Hagiwara

7
開始ページ
46126
終了ページ
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1038/srep46126
出版者・発行元
NATURE PUBLISHING GROUP

Duchenne muscular dystrophy (DMD) is a fatal progressive muscle-wasting disease. Various attempts are underway to convert severe DMD to a milder phenotype by modulating the splicing of the dystrophin gene and restoring its expression. In our previous study, we reported TG003, an inhibitor of CDC2-like kinase 1 (CLK1), as a splice-modifying compound for exon-skipping therapy; however, its metabolically unstable feature hinders clinical application. Here, we show an orally available inhibitor of CLK1, named TG693, which promoted the skipping of the endogenous mutated exon 31 in DMD patient-derived cells and increased the production of the functional exon 31-skipped dystrophin protein. Oral administration of TG693 to mice inhibited the phosphorylation of serine/arginine-rich proteins, which are the substrates of CLK1, and modulated pre-mRNA splicing in the skeletal muscle. Thus, TG693 is a splicing modulator for the mutated exon 31 of the dystrophin gene in vivo, possibly possessing therapeutic potential for DMD patients.

Web of Science ® 被引用回数 : 32

リンク情報
DOI
https://doi.org/10.1038/srep46126
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000402313100001&DestApp=WOS_CPL
ID情報
  • DOI : 10.1038/srep46126
  • ISSN : 2045-2322
  • Web of Science ID : WOS:000402313100001

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