无义突变是产生过早终止密码子(PTC)的基因突变,导致截断,囊性纤维化等疾病中的缺陷蛋白,神经纤维瘤病1型,Dravet综合征,Hurler综合征,β地中海贫血,遗传性骨髓衰竭综合征,杜氏肌营养不良症,甚至癌症。这些突变还可以触发细胞监视机制,称为无义介导的mRNA衰变(NMD),该机制会降解含PTC的mRNA。NMD的激活可以减弱截断的后果,有缺陷,和细胞中潜在的有毒蛋白质。由于所有单点突变中约有20%是致病的无义突变,这一领域受到广泛关注并不奇怪,近年来取得了显著进展。事实上,自从我们上次关于这个主题的评论以来,已经报道了无意义抑制方法的新例子,即促进PTCs翻译通读或抑制NMD途径的新途径。通过这次审查,我们在无稽之谈中更新了最先进的技术,专注于具有治疗潜力的新模式,例如小分子(透读剂,NMD抑制剂,和分子胶降解物);反义寡核苷酸;tRNA抑制子;ADAR介导的RNA编辑;靶向假尿嘧啶化;和基因/碱基编辑。虽然自我们上次审查以来,这些不同的模式在发展阶段有了显著的进步,每个都有优势(例如,易于交付和特异性)和缺点(制造复杂性和脱靶效应潜力),我们在这里讨论。
Nonsense mutations are genetic mutations that create premature termination codons (PTCs), leading to truncated, defective proteins in diseases such as cystic fibrosis, neurofibromatosis type 1, Dravet syndrome, Hurler syndrome, Beta thalassemia, inherited bone marrow failure syndromes, Duchenne muscular dystrophy, and even cancer. These mutations can also trigger a cellular surveillance mechanism known as nonsense-mediated mRNA decay (NMD) that degrades the PTC-containing mRNA. The activation of NMD can attenuate the consequences of truncated, defective, and potentially toxic proteins in the cell. Since approximately 20% of all single-point mutations are disease-causing nonsense mutations, it is not surprising that this field has received significant attention, resulting in a remarkable advancement in recent years. In fact, since our last review on this topic, new examples of nonsense suppression approaches have been reported, namely new ways of promoting the translational readthrough of PTCs or inhibiting the NMD pathway. With this review, we update the state-of-the-art technologies in nonsense suppression, focusing on novel modalities with therapeutic potential, such as small molecules (readthrough agents, NMD inhibitors, and molecular glue degraders); antisense
oligonucleotides; tRNA suppressors; ADAR-mediated RNA editing; targeted pseudouridylation; and gene/base editing. While these various modalities have significantly advanced in their development stage since our last review, each has advantages (e.g., ease of delivery and specificity) and disadvantages (manufacturing complexity and off-target effect potential), which we discuss here.