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Amelioration of intracellular Ca2+ regulation by exon-45 skipping in Duchenne muscular dystrophy-induced pluripotent stem cell-derived cardiomyocytes.
Biochem Biophys Res Commun. 2019 11 26; 520(1):179-185.BB

Abstract

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.

Authors+Show Affiliations

Third Department of Medicine, Shinshu University School of Medicine, Matsumoto, Nagano, 390-8621, Japan.Department of Regenerative Science and Medicine, Shinshu University, Matsumoto, Nagano, 390-8621, Japan.Third Department of Medicine, Shinshu University School of Medicine, Matsumoto, Nagano, 390-8621, Japan; Intractable Disease Care Center, Shinshu University Hospital, Matsumoto, Nagano, 390-8621, Japan.Department of Regenerative Science and Medicine, Shinshu University, Matsumoto, Nagano, 390-8621, Japan.Laboratory of Biomedical Science, Department of Veterinary Medicine, College of Bioresource Sciences, Nihon University, Fujisawa, Kanagawa 252-0880, Japan.Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, T6G 2H7, Canada.Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Kodaira, Tokyo, 187-8502, Japan.Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Kodaira, Tokyo, 187-8502, Japan.Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Kodaira, Tokyo, 187-8502, Japan.Third Department of Medicine, Shinshu University School of Medicine, Matsumoto, Nagano, 390-8621, Japan; Department of Clinical Research, National Hospital Organization Matsumoto Medical Center, Murai-Machi Minami, Matsumoto, 399-8701, Japan. Electronic address: anakamu@shinshu-u.ac.jp.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31585729

Citation

Sato, Mitsuto, et al. "Amelioration of Intracellular Ca2+ Regulation By Exon-45 Skipping in Duchenne Muscular Dystrophy-induced Pluripotent Stem Cell-derived Cardiomyocytes." Biochemical and Biophysical Research Communications, vol. 520, no. 1, 2019, pp. 179-185.
Sato M, Shiba N, Miyazaki D, et al. Amelioration of intracellular Ca2+ regulation by exon-45 skipping in Duchenne muscular dystrophy-induced pluripotent stem cell-derived cardiomyocytes. Biochem Biophys Res Commun. 2019;520(1):179-185.
Sato, M., Shiba, N., Miyazaki, D., Shiba, Y., Echigoya, Y., Yokota, T., Takizawa, H., Aoki, Y., Takeda, S., & Nakamura, A. (2019). Amelioration of intracellular Ca2+ regulation by exon-45 skipping in Duchenne muscular dystrophy-induced pluripotent stem cell-derived cardiomyocytes. Biochemical and Biophysical Research Communications, 520(1), 179-185. https://doi.org/10.1016/j.bbrc.2019.09.095
Sato M, et al. Amelioration of Intracellular Ca2+ Regulation By Exon-45 Skipping in Duchenne Muscular Dystrophy-induced Pluripotent Stem Cell-derived Cardiomyocytes. Biochem Biophys Res Commun. 2019 11 26;520(1):179-185. PubMed PMID: 31585729.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Amelioration of intracellular Ca2+ regulation by exon-45 skipping in Duchenne muscular dystrophy-induced pluripotent stem cell-derived cardiomyocytes. AU - Sato,Mitsuto, AU - Shiba,Naoko, AU - Miyazaki,Daigo, AU - Shiba,Yuji, AU - Echigoya,Yusuke, AU - Yokota,Toshifumi, AU - Takizawa,Hotake, AU - Aoki,Yoshitsugu, AU - Takeda,Shin'ichi, AU - Nakamura,Akinori, Y1 - 2019/10/01/ PY - 2019/09/04/received PY - 2019/09/22/accepted PY - 2019/10/6/pubmed PY - 2020/6/24/medline PY - 2019/10/6/entrez KW - Arrhythmic cell KW - Ca(2+) transient KW - Cardiomyocyte KW - Duchenne muscular dystrophy KW - Exon skipping KW - Induced-pluripotent stem cell SP - 179 EP - 185 JF - Biochemical and biophysical research communications JO - Biochem. Biophys. Res. Commun. VL - 520 IS - 1 N2 - 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. SN - 1090-2104 UR - https://www.unboundmedicine.com/medline/citation/31585729/Amelioration_of_intracellular_Ca2+_regulation_by_exon_45_skipping_in_Duchenne_muscular_dystrophy_induced_pluripotent_stem_cell_derived_cardiomyocytes_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0006-291X(19)31825-X DB - PRIME DP - Unbound Medicine ER -