In vivo genome editing improves muscle function in a mouse model of Duchenne muscular dystrophy.
In vivo genome editing improves muscle function in a mouse model of Duchenne muscular dystrophy.
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DOI：
10.1126/science.aad5143
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发表时间：
2016-01-22
期刊：
影响因子：
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通讯作者：
Gersbach CA
中科院分区：
文献类型：
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作者：
Nelson CE;Hakim CH;Ousterout DG;Thakore PI;Moreb EA;Castellanos Rivera RM;Madhavan S;Pan X;Ran FA;Yan WX;Asokan A;Zhang F;Duan D;Gersbach CA
杜氏肌营养不良症（DMD）是一种毁灭性的疾病，大约每5000名男性新生儿中就有1人患病，由抗肌萎缩蛋白基因的突变引起。基因组编辑有可能恢复经修饰的抗肌萎缩蛋白基因在其天然位点的表达，从而调节疾病进展。在这项研究中，腺相关病毒被用于将CRISPR/Cas9系统递送至DMD的mdx小鼠模型中，以从抗肌萎缩蛋白基因中去除突变的外显子23。这包括对成年小鼠的局部和全身递送以及对新生小鼠的全身递送。通过CRISPR/Cas9删除外显子23导致了经修饰的抗肌萎缩蛋白基因的表达，骨骼肌纤维和心肌中功能性抗肌萎缩蛋白的部分恢复，肌肉生化指标的改善以及肌肉力量的显著增强。这项工作确立了基于CRISPR/Cas9的基因组编辑作为治疗DMD的一种潜在疗法。
Duchenne muscular dystrophy (DMD) is a devastating disease affecting about 1 out of 5000 male births and caused by mutations in the dystrophin gene. Genome editing has the potential to restore expression of a modified dystrophin gene from the native locus to modulate disease progression. In this study, adeno-associated virus was used to deliver the CRISPR/Cas9 system to the mdx mouse model of DMD to remove the mutated exon 23 from the dystrophin gene. This includes local and systemic delivery to adult mice and systemic delivery to neonatal mice. Exon 23 deletion by CRISPR/Cas9 resulted in expression of the modified dystrophin gene, partial recovery of functional dystrophin protein in skeletal myofibers and cardiac muscle, improvement of muscle biochemistry, and significant enhancement of muscle force. This work establishes CRISPR/Cas9-based genome editing as a potential therapy to treat DMD.