Antisense oligonucleotides are an emerging therapeutic option to treat diseases with known genetic origin. In the age of personalised medicines, antisense oligonucleotides can sometimes be designed to target and bypass or overcome a patient’s genetic mutation, in particular those lesions that compromise normal pre-mRNA processing. Antisense oligonucleotides can alter gene expression through a variety of mechanisms as determined by the chemistry and antisense oligomer design. Through targeting the pre-mRNA, antisense oligonucleotides can alter splicing and induce a specific spliceoform or disrupt the reading frame, target an RNA transcript for degradation through RNaseH activation, block ribosome initiation of protein translation or disrupt miRNA function. The recent accelerated approval of eteplirsen (renamed Exondys 51™) by the Food and Drug Administration, for the treatment of Duchenne muscular dystrophy, and nusinersen, for the treatment of spinal muscular atrophy, herald a new and exciting era in splice-switching antisense oligonucleotide applications to treat inherited diseases. This review considers the potential of antisense oligonucleotides to treat inherited lung diseases of childhood with a focus on cystic fibrosis and disorders of surfactant protein metabolism.

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反义寡核苷酸疗法治疗遗传性儿童肺部疾病的潜力


反义寡核苷酸是一种新兴的治疗选择，用于治疗已知遗传起源的疾病。在个性化医疗时代，反义寡核苷酸有时可以被设计为靶向并绕过或克服患者的基因突变，特别是那些损害正常前 mRNA 加工的病变。反义寡核苷酸可以通过化学和反义寡聚物设计确定的多种机制改变基因表达。通过靶向前 mRNA，反义寡核苷酸可以改变剪接并诱导特定的剪接形式或破坏阅读框，靶向 RNA 转录物以通过 RNaseH 激活进行降解，阻止核糖体启动蛋白质翻译或破坏 miRNA 功能。最近，美国食品和药物管理局加速批准用于治疗杜氏肌营养不良症的 eteplirsen（更名为 Exondys 51™）和用于治疗脊髓性肌萎缩症的 nusinersen，预示着剪接转换反义寡核苷酸进入了令人兴奋的新时代治疗遗传性疾病的应用。本综述考虑了反义寡核苷酸治疗儿童遗传性肺部疾病的潜力，重点关注囊性纤维化和表面活性剂蛋白代谢紊乱。