基因组编辑
清脆的
杜氏肌营养不良
Cas9
骨骼肌
免疫原性
肌营养不良蛋白
mdx鼠标
亚基因组mRNA
引导RNA
肌营养不良
外显子跳跃
医学
外显子
生物
遗传学
抗体
基因
解剖
选择性拼接
作者
Eriya Kenjo,Hiroyuki Hozumi,Yukimasa Makita,Kumiko A. Iwabuchi,Naoko Fujimoto,Satoru Matsumoto,Maya Kimura,Yuichiro Amano,Masataka Ifuku,Youichi Naoe,Naoto Inukai,Akitsu Hotta
标识
DOI:10.1038/s41467-021-26714-w
摘要
Genome editing therapy for Duchenne muscular dystrophy (DMD) holds great promise, however, one major obstacle is delivery of the CRISPR-Cas9/sgRNA system to skeletal muscle tissues. In general, AAV vectors are used for in vivo delivery, but AAV injections cannot be repeated because of neutralization antibodies. Here we report a chemically defined lipid nanoparticle (LNP) system which is able to deliver Cas9 mRNA and sgRNA into skeletal muscle by repeated intramuscular injections. Although the expressions of Cas9 protein and sgRNA were transient, our LNP system could induce stable genomic exon skipping and restore dystrophin protein in a DMD mouse model that harbors a humanized exon sequence. Furthermore, administration of our LNP via limb perfusion method enables to target multiple muscle groups. The repeated administration and low immunogenicity of our LNP system are promising features for a delivery vehicle of CRISPR-Cas9 to treat skeletal muscle disorders.
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