杜氏肌营养不良症基因治疗新进展

New Advances in Gene Therapy for Duchenne Muscular Dystrophy

杜氏肌营养不良症(DMD)是由于抗肌萎缩蛋白缺乏引起的X连锁隐性遗传性神经肌肉病。目前,DMD尚无有效治疗手段,基因替代、外显子跳跃、基因组编辑、终止密码子通读等基因治疗逐步成为研究热点。基因替代治疗利用腺相关病毒介导的微型抗肌萎缩蛋白导入已在动物模型中得到证实;外显子跳跃可通过跳跃1到2个特定的外显子来恢复阅读框进而可治疗80%的DMD患者,其中Eteplirsen是针对51号外显子的反义寡核苷酸,已经通过FDA批准。基因组编辑技术仍处于体外细胞和动物实验阶段,应用于人体的安全性和有效性还需临床进一步试验证实。终止密码通读治疗适用于所有无义突变的DMD患者,占总患者人群的10%~15%。2014年EMA对年龄≥5岁的无义突变患者予以有条件批准使用Ataluren治疗。DMD的基因治疗发展迅速,整体前景令人期待;但应用于临床仍需克服许多障碍,还需进一步优化和更多的研究支持。

Duchenne muscular dystrophy(DMD)is an X-linked recessive hereditary neuromuscular disease caused by dystrophin deficiency.Currently,there is no effective treatment for DMD,and gene therapy such as gene replacement,exon skipping,genome editing,stop codon read-through therapy has gradually become a research focus.Gene replacement therapy using adeno-associated virus-mediated mini-dystrophin-introduction therapy has been confirmed in animal models;exon skipping therapy can restore reading frame by skipping 1 to 2 specific exons to treat 80%of DMD patients,among which Eteplirsen,an antisense oligonucleotide targeting exon 51,has been approved by the FDA.The use of genome editing technology is still in the stage of in vitro cell and animal experiments,and further clinical trials are needed to confirm its safety and effectiveness in humans.The stop code read-through therapy is applicable to all patients with nonsense mutation DMD,accounting for about 10%to 15%of the total patient population.In 2014,EMA granted conditional approval to use Ataluren for nonsense mutation patients aged≥5 years.The gene therapy of DMD is developing rapidly,and the overall prospect is promising,but it still needs to overcome many obstacles,further optimization and more research support for clinical application.