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Exon Skipping Therapy Using Phosphorodiamidate Morpholino Oligomers in the mdx52 Mouse Model of Duchenne Muscular Dystrophy.
Methods Mol Biol. 2018; 1687:123-141.MM

Abstract

Exon skipping therapy using synthetic DNA-like molecules called antisense oligonucleotides (ASOs) is a promising therapeutic candidate for overcoming the dystrophin mutation that causes Duchenne muscular dystrophy (DMD). This treatment involves splicing out the frame-disrupting segment of the dystrophin mRNA, which restores the reading frame and produces a truncated yet functional dystrophin protein. Phosphorodiamidate morpholino oligomer (PMO) is the safest ASO for patients among ASOs and has recently been approved under the accelerated approval pathway by the U.S. Food and Drug Administration (FDA) as the first drug for DMD. Here, we describe the methodology and protocol of PMO transfection and evaluation of the exon skipping efficacy in the mdx52 mouse, an exon 52 deletion model of DMD produced by gene targeting. The mdx52 mouse model offers advantages over the mdx mouse, a spontaneous DMD model with a nonsense mutation in exon 23, in terms of the deletion in a hotspot of deletion mutations in DMD patients, the analysis of caveolae and also Dp140 and Dp260, shorter dystrophin isoforms.

Authors+Show Affiliations

Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-higashi, Kodaira, Tokyo, 187-8551, Japan.Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-higashi, Kodaira, Tokyo, 187-8551, Japan.Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-higashi, Kodaira, Tokyo, 187-8551, Japan.Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-higashi, Kodaira, Tokyo, 187-8551, Japan.Department of Medical Genetics, University of Alberta Faculty of Medicine and Dentistry, Edmonton, AB, Canada, T6G 2H7.Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-higashi, Kodaira, Tokyo, 187-8551, Japan.Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-higashi, Kodaira, Tokyo, 187-8551, Japan. tsugu56@ncnp.go.jp.

Pub Type(s)

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

Language

eng

PubMed ID

29067660

Citation

Miyatake, Shouta, et al. "Exon Skipping Therapy Using Phosphorodiamidate Morpholino Oligomers in the Mdx52 Mouse Model of Duchenne Muscular Dystrophy." Methods in Molecular Biology (Clifton, N.J.), vol. 1687, 2018, pp. 123-141.
Miyatake S, Mizobe Y, Takizawa H, et al. Exon Skipping Therapy Using Phosphorodiamidate Morpholino Oligomers in the mdx52 Mouse Model of Duchenne Muscular Dystrophy. Methods Mol Biol. 2018;1687:123-141.
Miyatake, S., Mizobe, Y., Takizawa, H., Hara, Y., Yokota, T., Takeda, S., & Aoki, Y. (2018). Exon Skipping Therapy Using Phosphorodiamidate Morpholino Oligomers in the mdx52 Mouse Model of Duchenne Muscular Dystrophy. Methods in Molecular Biology (Clifton, N.J.), 1687, 123-141. https://doi.org/10.1007/978-1-4939-7374-3_9
Miyatake S, et al. Exon Skipping Therapy Using Phosphorodiamidate Morpholino Oligomers in the Mdx52 Mouse Model of Duchenne Muscular Dystrophy. Methods Mol Biol. 2018;1687:123-141. PubMed PMID: 29067660.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Exon Skipping Therapy Using Phosphorodiamidate Morpholino Oligomers in the mdx52 Mouse Model of Duchenne Muscular Dystrophy. AU - Miyatake,Shouta, AU - Mizobe,Yoshitaka, AU - Takizawa,Hotake, AU - Hara,Yuko, AU - Yokota,Toshifumi, AU - Takeda,Shin'ichi, AU - Aoki,Yoshitsugu, PY - 2017/10/26/entrez PY - 2017/10/27/pubmed PY - 2018/6/6/medline KW - Duchenne/becker muscular dystrophies (DMD/BMD) KW - Dystrophin KW - Exon skipping KW - Phosphorodiamidate morpholino oligomer (PMO) KW - mdx KW - mdx52 SP - 123 EP - 141 JF - Methods in molecular biology (Clifton, N.J.) JO - Methods Mol Biol VL - 1687 N2 - Exon skipping therapy using synthetic DNA-like molecules called antisense oligonucleotides (ASOs) is a promising therapeutic candidate for overcoming the dystrophin mutation that causes Duchenne muscular dystrophy (DMD). This treatment involves splicing out the frame-disrupting segment of the dystrophin mRNA, which restores the reading frame and produces a truncated yet functional dystrophin protein. Phosphorodiamidate morpholino oligomer (PMO) is the safest ASO for patients among ASOs and has recently been approved under the accelerated approval pathway by the U.S. Food and Drug Administration (FDA) as the first drug for DMD. Here, we describe the methodology and protocol of PMO transfection and evaluation of the exon skipping efficacy in the mdx52 mouse, an exon 52 deletion model of DMD produced by gene targeting. The mdx52 mouse model offers advantages over the mdx mouse, a spontaneous DMD model with a nonsense mutation in exon 23, in terms of the deletion in a hotspot of deletion mutations in DMD patients, the analysis of caveolae and also Dp140 and Dp260, shorter dystrophin isoforms. SN - 1940-6029 UR - https://www.unboundmedicine.com/medline/citation/29067660/Exon_Skipping_Therapy_Using_Phosphorodiamidate_Morpholino_Oligomers_in_the_mdx52_Mouse_Model_of_Duchenne_Muscular_Dystrophy_ L2 - https://dx.doi.org/10.1007/978-1-4939-7374-3_9 DB - PRIME DP - Unbound Medicine ER -