Gene editing and muscular dystrophy Duchenne muscular dystrophy (DMD) is characterized by progressive muscle weakness and a shortened life span. The disease is caused by mutations that reduce or prevent expression of dystrophin, an essential structural protein in skeletal and heart muscle. The gene editing technology CRISPR-Cas9 can correct disease-causing mutations and has yielded promising results in mouse models of DMD. In a small, short-term study, Amoasii et al. tested this strategy in a dog model of DMD that exhibits many features of the human disease. Intramuscular or systemic delivery of the gene editing components resulted in a substantial increase in dystrophin protein levels in skeletal and heart muscle. Restoration of dystrophin expression was accompanied by improved muscle histology. Science, this issue p. 86 Successful CRISPR correction of a dystrophin mutation in dogs increases dystrophin protein expression in skeletal and heart muscle. Mutations in the gene encoding dystrophin, a protein that maintains muscle integrity and function, cause Duchenne muscular dystrophy (DMD). The deltaE50-MD dog model of DMD harbors a mutation corresponding to a mutational “hotspot” in the human DMD gene. We used adeno-associated viruses to deliver CRISPR gene editing components to four dogs and examined dystrophin protein expression 6 weeks after intramuscular delivery (n = 2) or 8 weeks after systemic delivery (n = 2). After systemic delivery in skeletal muscle, dystrophin was restored to levels ranging from 3 to 90% of normal, depending on muscle type. In cardiac muscle, dystrophin levels in the dog receiving the highest dose reached 92% of normal. The treated dogs also showed improved muscle histology. These large-animal data support the concept that, with further development, gene editing approaches may prove clinically useful for the treatment of DMD.

中文翻译：

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基因编辑可恢复杜氏肌营养不良症犬模型中的肌营养不良蛋白表达

基因编辑和肌营养不良症 Duchenne 肌营养不良症 (DMD) 的特点是进行性肌肉无力和寿命缩短。这种疾病是由降低或阻止肌营养不良蛋白表达的突变引起的，肌营养不良蛋白是骨骼肌和心肌中的一种基本结构蛋白。基因编辑技术 CRISPR-Cas9 可以纠正致病突变，并在 DMD 小鼠模型中取得了可喜的成果。在一项小型短期研究中，Amoasii 等人。在 DMD 狗模型中测试了这种策略，该模型表现出人类疾病的许多特征。基因编辑成分的肌内或全身递送导致骨骼肌和心肌中肌营养不良蛋白水平的显着增加。肌营养不良蛋白表达的恢复伴随着肌肉组织学的改善。科学，这个问题 p。86 犬肌营养不良蛋白突变的成功 CRISPR 校正增加了骨骼肌和心肌中肌营养不良蛋白的表达。编码抗肌萎缩蛋白（一种维持肌肉完整性和功能的蛋白质）的基因发生突变，导致杜氏肌营养不良症 (DMD)。DMD 的 deltaE50-MD 狗模型包含与人类 DMD 基因中的突变“热点”相对应的突变。我们使用腺相关病毒将 CRISPR 基因编辑组件传递给四只狗，并在肌肉注射后 6 周（n = 2）或全身分娩后 8 周（n = 2）检查了肌营养不良蛋白的表达。在骨骼肌中全身给药后，肌营养不良蛋白恢复到正常水平的 3% 至 90%，具体取决于肌肉类型。在心肌中，接受最高剂量的狗的肌营养不良蛋白水平达到正常值的 92%。接受治疗的狗也表现出改善的肌肉组织学。这些大型动物数据支持这样一个概念，即随着进一步的发展，基因编辑方法可能会证明在临床上对 DMD 的治疗有用。