Extensive and Prolonged Restoration of Dystrophin Expression with Vivo-Morpholino-Mediated Multiple Exon Skipping in Dystrophic Dogs
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- Toshifumi Yokota
- University of Alberta
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- Akinori Nakamura
- National Institute of Neuroscience
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- Tetsuya Nagata
- National Institute of Neuroscience
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- Takashi Saito
- National Institute of Neuroscience
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- Masanori Kobayashi
- National Institute of Neuroscience
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- Yoshitsugu Aoki
- National Institute of Neuroscience
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- Yusuke Echigoya
- University of Alberta
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- Terence Partridge
- Children's National Medical Center
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- Eric P. Hoffman
- Children's National Medical Center
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- Shin'ichi Takeda
- National Institute of Neuroscience
書誌事項
- 公開日
- 2012-08-13
- 資源種別
- journal article
- 権利情報
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- https://creativecommons.org/licenses/by/4.0/
- https://journals.sagepub.com/page/policies/text-and-data-mining-license
- DOI
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- 10.1089/nat.2012.0368
- 公開者
- SAGE Publications
この論文をさがす
説明
<jats:p> Duchenne muscular dystrophy (DMD) is a severe and the most prevalent form of muscular dystrophy, characterized by rapid progression of muscle degeneration. Antisense-mediated exon skipping is currently one of the most promising therapeutic options for DMD. However, unmodified antisense oligos such as morpholinos require frequent (weekly or bi-weekly) injections. Recently, new generation morpholinos such as vivo-morpholinos are reported to lead to extensive and prolonged dystrophin expression in the dystrophic <jats:italic toggle="yes">mdx</jats:italic> mouse, an animal model of DMD. The vivo-morpholino contains a cell-penetrating moiety, octa-guanidine dendrimer. Here, we sought to test the efficacy of multiple exon skipping of exons 6–8 with vivo-morpholinos in the canine X-linked muscular dystrophy, which harbors a splice site mutation at the boundary of intron 6 and exon 7. We designed and optimized novel antisense cocktail sequences and combinations for exon 8 skipping and demonstrated effective exon skipping in dystrophic dogs <jats:italic toggle="yes">in vivo</jats:italic> . Intramuscular injections with newly designed cocktail oligos led to high levels of dystrophin expression, with some samples similar to wild-type levels. This is the first report of successful rescue of dystrophin expression with morpholino conjugates in dystrophic dogs. Our results show the potential of phosphorodiamidate morpholino oligomer conjugates as therapeutic agents for DMD. </jats:p>
収録刊行物
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- Nucleic Acid Therapeutics
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Nucleic Acid Therapeutics 22 (5), 306-315, 2012-08-13
SAGE Publications