Verma Ashok
Department of Neurology, Don Soffer Clinical Research Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA.
Ann Indian Acad Neurol. 2018 Jan-Mar;21(1):3-8. doi: 10.4103/aian.AIAN_298_17.
Genetic neuromuscular diseases are caused by defective expression of nuclear or mitochondrial genes. Mutant genes may reduce expression of wild-type proteins, and strategies to activate expression of the wild-type proteins might provide therapeutic benefits. Also, a toxic mutant protein may cause cell death, and strategies that reduce mutant gene expression may provide therapeutic benefit. Synthetic antisense oligonucleotide (ASO) can recognize cellular RNA and control gene expression. In recent years, advances in ASO chemistry, creation of designer ASO molecules to enhance their safety and target delivery, and scientific controlled clinical trials to ascertain their therapeutic safety and efficacy have led to an era of plausible application of ASO technology to treat currently incurable neuromuscular diseases. Over the past 1 year, for the first time, the United States Food and Drug Administration has approved two ASO therapies in genetic neuromuscular diseases. This overview summarizes the recent advances in ASO technology, evolution and use of synthetic ASOs as a therapeutic platform, and the mechanism of ASO action by exon-skipping in Duchenne muscular dystrophy and exon-inclusion in spinal muscular atrophy, with comments on their advantages and limitations.
遗传性神经肌肉疾病是由核基因或线粒体基因的缺陷表达引起的。突变基因可能会减少野生型蛋白的表达，而激活野生型蛋白表达的策略可能会带来治疗益处。此外，有毒的突变蛋白可能导致细胞死亡，减少突变基因表达的策略可能会提供治疗益处。合成反义寡核苷酸（ASO）可以识别细胞RNA并控制基因表达。近年来，ASO化学的进展、设计用于提高其安全性和靶向递送的ASO分子的创建，以及确定其治疗安全性和有效性的科学对照临床试验，已开创了一个将ASO技术合理应用于治疗目前无法治愈的神经肌肉疾病的时代。在过去1年里，美国食品药品监督管理局首次批准了两种用于遗传性神经肌肉疾病的ASO疗法。本综述总结了ASO技术的最新进展、合成ASO作为治疗平台的演变和应用，以及ASO在杜氏肌营养不良症中通过外显子跳跃和在脊髓性肌萎缩症中通过外显子包含发挥作用的机制，并对其优缺点进行了评论。
