title: Contributions of Japanese patients to development of antisense therapy for DMD.
abstract: BACKGROUND
  Duchenne muscular dystrophy (DMD) is a fatal progressive muscle wasting disease considered untreatable since its first description in 1868. In 1987, the dystrophin gene responsible for DMD was cloned. This paved the way for the development of therapies. Antisense oligonucleotide (AO)-mediated exon skipping therapy is now reaching the stage of marketing authorization. On the 20th anniversary of the proposal of AO-mediated exon skipping therapy for DMD, this review explores the contributions of Japanese patients.
  
  
  RESULTS
  In 1990, a Japanese DMD patient was reported as having a small deletion within dystrophin exon 19 and complicating exon 19 skipping in the absence of any mutation at the consensus splice sites. This led to identification of a splicing enhancer sequence within exon 19. Remarkably, AOs against this sequence were shown to induce exon skipping. This encouraged us to propose AO-mediated exon skipping therapy for DMD in 1995. The therapy's effectiveness was verified in a Japanese patient with a nonsense dystrophin mutation manifesting as Becker muscular dystrophy. The patient showed skipping of the nonsense mutation-encoding exon. Finally, a DMD patient carrying a deletion of exon 20 volunteered to undergo intravenous AO infusion, enabling us to obtain proof of concept. The findings from these three patients greatly facilitated studies on exon skipping therapy. As a result, more than 300 reports on AO-mediated exon skipping therapy for DMD have been published, including at least two a month during the last few years.
  
  
  CONCLUSIONS
  We greatly appreciate the important contributions of Japanese patients to development of the exon skipping therapy for DMD.
authors.affiliation: Department of Medical Rehabilitation, Faculty of Rehabilitation, Kobe Gakuin University, Japan. Electronic address: mmatsuo@reha.kobegakuin.ac.jp.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Matsuo
authors.affiliation: Department of Pediatrics, Hyogo College of Medicine, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Takeshima
authors.affiliation: Department of Community Medicine and Social Healthcare Science, Kobe University Graduate School of Medicine, Japan.
authors.forename: Hisahide
authors.initials: H
authors.lastname: Nishio
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D016189:Dystrophin / Q000235:genetics*; D005091:Exons; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007564:Japan; D008297:Male; D020388:Muscular Dystrophy, Duchenne / Q000235:genetics* / Q000628:therapy*; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*
chemical_list: C484258:DMD protein, human; D016189:Dystrophin; D016376:Oligonucleotides, Antisense
keywords: Antisense oligonucleotide; Becker muscular dystrophy; Duchenne muscular dystrophy; Exon skipping; Reading frame; Treatment