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Koo, Taeyoung,Lu-Nguyen, Ngoc B.,Malerba, Alberto,Kim, Eunji,Kim, Daesik,Cappellari, Ornella,Cho, Hee-Yeon,Dickson, George,Popplewell, Linda,Kim, Jin-Soo American Society of GeneCell Therapy 2018 Molecular therapy Vol.26 No.6
<▼1><P>Duchenne muscular dystrophy (DMD) is a fatal, X-linked muscle-wasting disease caused by mutations in the <I>DMD</I> gene. In 51% of DMD cases, a reading frame is disrupted because of deletion of several exons. Here, we show that CjCas9 derived from <I>Campylobacter jejuni</I> can be used as a gene-editing tool to correct an out-of-frame <I>Dmd</I> exon in <I>Dmd</I> knockout mice. Herein, we used Cas9 derived from <I>S. pyogenes</I> to generate <I>Dmd</I> knockout mice with a frameshift mutation in <I>Dmd</I> gene. Then, we expressed CjCas9, its single-guide RNA, and the EGFP gene in the <I>tibialis anterior</I> muscle of the <I>Dmd</I> knockout mice using an all-in-one adeno-associated virus (AAV) vector. CjCas9 cleaved the target site in the <I>Dmd</I> gene efficiently <I>in vivo</I> and induced small insertions or deletions at the target site. This treatment resulted in conversion of the disrupted <I>Dmd</I> reading frame from out of frame to in frame, leading to the expression of dystrophin in the sarcolemma. Importantly, muscle strength was enhanced in the CjCas9-treated muscles, without off-target mutations, indicating high efficiency and specificity of CjCas9. This work suggests that <I>in vivo DMD</I> frame correction, mediated by CjCas9, has great potential for the treatment of DMD and other neuromuscular diseases.</P></▼1><▼2><P>Koo et al. demonstrate that CjCas9 derived from <I>Campylobacter jejuni</I> can be used as a gene-editing tool to correct an out-of-frame <I>Dmd</I> exon in <I>Dmd</I> knockout mice. This study provides the therapeutic utility of CjCas9 for the treatment of Duchenne muscular dystrophy and other neuromuscular diseases.</P></▼2>