title: Long-term efficacy of systemic multiexon skipping targeting dystrophin exons 45-55 with a cocktail of vivo-morpholinos in mdx52 mice.
abstract: Antisense-mediated exon skipping, which can restore the reading frame, is a most promising therapeutic approach for Duchenne muscular dystrophy. Remaining challenges include the limited applicability to patients and unclear function of truncated dystrophin proteins. Multiexon skipping targeting exons 45-55 at the mutation hotspot of the dystrophin gene could overcome both of these challenges. Previously, we described the feasibility of exons 45-55 skipping with a cocktail of Vivo-Morpholinos in vivo; however, the long-term efficacy and safety of Vivo-Morpholinos remains to be determined. In this study, we examined the efficacy and toxicity of exons 45-55 skipping by intravenous injections of 6 mg/kg 10-Vivo-Morpholino cocktail (0.6 mg/kg each vPMO) every 2 weeks for 18 weeks to dystrophic exon-52 knockout (mdx52) mice. Systemic skipping of the entire exons 45-55 region was induced, and the Western blot analysis exhibited the restoration of 5-27% of normal levels of dystrophin protein in skeletal muscles, accompanied by improvements in histopathology and muscle strength. No obvious immune response and renal and hepatic toxicity were detected at the end-point of the treatment. We demonstrate our new regimen with the 10-Vivo-Morpholino cocktail is effective and safe for long-term repeated systemic administration in the dystrophic mouse model.
authors: Department of Medical Genetics, School of Human Development, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
authors: Yusuke
authors: Y
authors: Echigoya
authors: 1] Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Kodaira, Japan [2] Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
authors: Yoshitsugu
authors: Y
authors: Aoki
authors: Department of Medical Genetics, School of Human Development, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
authors: Bailey
authors: B
authors: Miskew
authors: Department of Medical Genetics, School of Human Development, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
authors: Dharminder
authors: D
authors: Panesar
authors: Department of Medical Genetics, School of Human Development, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
authors: Aleksander
authors: A
authors: Touznik
authors: Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Kodaira, Japan.
authors: Tetsuya
authors: T
authors: Nagata
authors: Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Kodaira, Japan.
authors: Jun
authors: J
authors: Tanihata
authors: Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Matsumoto, Japan.
authors: Akinori
authors: A
authors: Nakamura
authors: Center for Genetic Medicine Research, Children's National Medical Center, Washington DC, USA.
authors: Kanneboyina
authors: K
authors: Nagaraju
authors: 1] Department of Medical Genetics, School of Human Development, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada [2] Muscular Dystrophy Canada Research Chair, Edmonton, Alberta, Canada.
authors: Toshifumi
authors: T
authors: Yokota
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