Journal
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Volume 520, Issue 1, Pages 179-185Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2019.09.095
Keywords
Duchenne muscular dystrophy; Induced-pluripotent stem cell; Cardiomyocyte; Exon skipping; Ca2+ transient; Arrhythmic cell
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Funding
- Intramural Research Grant for Neurological and Psychiatric Disorders of the National Center of Neurology and Psychiatry [29-3]
- JSPS KAKENHI [15H04756, 18H02577, 18K15026]
- AMED [JP18ek0109357h0001]
- Grants-in-Aid for Scientific Research [15H04756, 18K15026, 18H02577] Funding Source: KAKEN
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Duchenne muscular dystrophy (DMD) is a devastating muscle disorder caused by frameshift mutations in the DMD gene. DMD involves cardiac muscle, and the presence of ventricular arrhythmias or congestive failure is critical for prognosis. Several novel therapeutic approaches are being evaluated in ongoing clinical trials. Among them, exon-skipping therapy to correct frameshift mutations with antisense oligonucleotides is promising; however, their therapeutic efficacies on cardiac muscle in vivo remain unknown. In this study, we established induced-pluripotent stem cells (iPSCs) from T cells from a DMD patient carrying a DMD-exon 46-55 deletion, differentiated the iPSCs into cardiomyocytes, and treated them with phosphorodiamidate morpholino oligomers. The efficiency of exon-45 skipping increased in a dose-dependent manner and enabled restoration of the DMD gene product, dystrophin. Further, Ca2+-imaging analysis showed a decreased number of arrhythmic cells and improved transient Ca(2+)signaling after exon skipping. Thus, exon-45 skipping may be effective for cardiac involvement in DMD patients harboring the DMD-exon 46-55 deletion. (C) 2019 The Authors. Published by Elsevier Inc.
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