Antisense PMO cocktails effectively skip dystrophin exons 45-55 in myotubes transdifferentiated from DMD patient fibroblasts

Joshua Lee, Yusuke Echigoya, William Duddy, Takashi Saito, Yoshitsugu Aoki, Shin’ichi Takeda, Toshifumi Yokota

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Abstract

Antisense-mediated exon skipping has made significant progress as a therapeutic platform in recent years, especially in the case of Duchenne muscular dystrophy (DMD). Despite FDA approval of eteplirsen–the first-ever antisense drug clinically marketed for DMD–exon skipping therapy still faces the significant hurdles of limited applicability and unknown truncated protein function. In-frame exon skipping of dystrophin exons 45–55 represents a significant approach to treating DMD, as a large proportion of patients harbor mutations within this “hotspot” region. Additionally, patients harboring dystrophin exons 45–55 deletion mutations are reported to have exceptionally mild to asymptomatic phenotypes. Here, we demonstrate that a cocktail of phosphorodiamidate morpholino oligomers can effectively skip dystrophin exons 45–55 in vitro in myotubes transdifferentiated from DMD patient fibroblast cells. This is the first report of substantive exons 45–55 skipping in DMD patient cells. These findings help validate the use of transdifferentiated patient fibroblast cells as a suitable cell model for dystrophin exon skipping assays and further emphasize the feasibility of dystrophin exons 45–55 skipping in patients.
Original languageEnglish
Article number0197084
Number of pages10
JournalPLoS ONE
Volume13
Issue number5
DOIs
Publication statusPublished - 17 May 2018

Keywords

  • Duchenne muscular dystrophy (DMD)
  • Exon skipping

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