Neuroscience Graduate Program, University of Michigan, Ann Arbor, Michigan, USA.
Department of Human Genetics, University of Michigan, Ann Arbor, Michigan, USA.
Dev Neurosci. 2021;43(3-4):247-252. doi: 10.1159/000517686. Epub 2021 Aug 5.
Antisense oligonucleotides (ASOs) are short oligonucleotides that can modify gene expression and mRNA splicing in the nervous system. The FDA has approved ASOs for treatment of ten genetic disorders, with many applications currently in the pipeline. We describe the molecular mechanisms of ASO treatment for four neurodevelopmental and neuromuscular disorders. The ASO nusinersen is a general treatment for mutations of SMN1 in spinal muscular atrophy that corrects the splicing defect in the SMN2 gene. Milasen is a patient-specific ASO that rescues splicing of CNL7 in Batten's disease. STK-001 is an ASO that increases expression of the sodium channel gene SCN1A by exclusion of a poison exon. An ASO that reduces the abundance of the SCN8A mRNA is therapeutic in mouse models of developmental and epileptic encephalopathy. These examples demonstrate the variety of mechanisms and range of applications of ASOs for treatment of neurodevelopmental disorders.
反义寡核苷酸（ASO）是一种短的寡核苷酸，可以修饰神经系统中的基因表达和 mRNA 剪接。FDA 已批准 ASO 用于治疗十种遗传疾病，目前有许多应用正在研发中。我们描述了 ASO 治疗四种神经发育和神经肌肉疾病的分子机制。ASO nusinersen 是一种用于治疗脊髓性肌萎缩症中 SMN1 突变的通用疗法，可纠正 SMN2 基因的剪接缺陷。Milasen 是一种针对 Batten 病中 CNL7 剪接的患者特异性 ASO。STK-001 是一种通过排除毒exon 来增加钠离子通道基因 SCN1A 表达的 ASO。减少 SCN8A mRNA 丰度的 ASO 在发育性和癫痫性脑病的小鼠模型中具有治疗作用。这些例子展示了 ASO 用于治疗神经发育障碍的多种机制和应用范围。
