Amelioration of intracellular Ca2+ regulation by exon-45 skipping in Duchenne muscular dystrophy-induced pluripotent stem cell-derived cardiomyocytes

• Published in: Biochemical and biophysical research communications Vol. 520; no. 1; pp. 179 - 185
• Main Authors: Sato, Mitsuto, Shiba, Naoko, Miyazaki, Daigo, Shiba, Yuji, Echigoya, Yusuke, Yokota, Toshifumi, Takizawa, Hotake, Aoki, Yoshitsugu, Takeda, Shin’ichi, Nakamura, Akinori
• Format: Journal Article
• Language: English
• Published: Elsevier Inc 26.11.2019
• Subjects: Arrhythmic cell; Ca2+ transient; Cardiomyocyte; Duchenne muscular dystrophy; Exon skipping; Induced-pluripotent stem cell; Ca2+ transient; Induced-pluripotent stem cell; Arrhythmic cell; Duchenne muscular dystrophy; Cardiomyocyte; Exon skipping
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2019.09.095

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 Ca2+ signaling after exon skipping. Thus, exon-45 skipping may be effective for cardiac involvement in DMD patients harboring the DMD-exon 46–55 deletion. •DMD causes muscle weakness, cardiomyopathy, and arrhythmia, which can be fatal.•DMD exon-45 skipping was performed with a PMO and iPSC-derived cardiomyocytes.•Exon-45 skipping restored dystrophin expression with the DMD exon-46–55 deletion.•The cardiomyocytes showed improved Ca2+ transients and decreased arrhythmia.•Exon-45 skipping may help treat DMD cardiac disorders, especially arrhythmia.