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유전체교정 연구단
유전체 교정 연구단
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Functional Rescue of Dystrophin Deficiency in Mice Caused by Frameshift Mutations Using Campylobacter jejuni Cas9

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Title
Functional Rescue of Dystrophin Deficiency in Mice Caused by Frameshift Mutations Using Campylobacter jejuni Cas9
Author(s)
Taeyoung Koo; Ngoc B. Lu-Nguyen; Alberto Malerba; Eunji Kim; Daesik Kim; Ornella Cappellari; Hee-Yeon Cho; George Dickson; Linda Popplewell; Jin-Soo Kim
Publication Date
2018-06
Journal
MOLECULAR THERAPY, v.26, no.6, pp.1529 - 1538
Publisher
NATURE PUBLISHING GROUP
Abstract
Duchenne muscular dystrophy (DMD) is a fatal, X-linked muscle-wasting disease caused by mutations in the DMD gene. In 51% of DMD cases, a reading frame is disrupted because of deletion of several exons. Here, we show that CjCas9 derived from Campylobacter jejuni can be used as a gene-editing tool to correct an out-of-frame Dmd exon in Dmd knockout mice. Herein, we used Cas9 derived from S. pyogenes to generate Dmd knockout mice with a frameshift mutation in Dmd gene. Then, we expressed CjCas9, its single-guide RNA, and the EGFP gene in the tibialis anterior muscle of the Dmd knockout mice using an all-in-one adeno-associated virus (AAV) vector. CjCas9 cleaved the target site in the Dmd gene efficiently in vivo and induced small insertions or deletions at the target site. This treatment resulted in conversion of the disrupted Dmd 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 in vivo DMD frame correction, mediated by CjCas9, has great potential for the treatment of DMD and other neuromuscular diseases. Koo et al. demonstrate that CjCas9 derived from Campylobacter jejuni can be used as a gene-editing tool to correct an out-of-frame Dmd exon in Dmd knockout mice. This study provides the therapeutic utility of CjCas9 for the treatment of Duchenne muscular dystrophy and other neuromuscular diseases. © 2018 The Author
URI
https://pr.ibs.re.kr/handle/8788114/4492
ISSN
1525-0016
Appears in Collections:
Center for Genome Engineering(유전체 교정 연구단) > Journal Papers (저널논문)
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