PTC Therapeutics, Inc., South Plainfield, New Jersey 07080, USA.
Annu Rev Med. 2013;64:407-25. doi: 10.1146/annurev-med-120611-144851. Epub 2012 Nov 28.
The interplay of translation and mRNA turnover has helped unveil how the regulation of gene expression is a continuum in which events that occur during the birth of a transcript in the nucleus can have profound effects on subsequent steps in the cytoplasm. Exemplifying this continuum is nonsense-mediated mRNA decay (NMD), the process wherein a premature stop codon affects both translation and mRNA decay. Studies of NMD helped lead us to the therapeutic concept of treating a subset of patients suffering from multiple genetic disorders due to nonsense mutations with a single small-molecule drug that modulates the translation termination process at a premature nonsense codon. Here we review both translation termination and NMD, and our subsequent efforts over the past 15 years that led to the identification, characterization, and clinical testing of ataluren, a new therapeutic with the potential to treat a broad range of genetic disorders due to nonsense mutations.
翻译和 mRNA 周转率的相互作用帮助揭示了基因表达的调控是一个连续的过程，核内转录本生成过程中发生的事件可以对细胞质中的后续步骤产生深远的影响。无意义介导的 mRNA 降解（NMD）就是一个很好的例子，其中一个过早的终止密码子会影响翻译和 mRNA 降解。对 NMD 的研究使我们产生了这样一个治疗理念，即对于由于无意义突变而患有多种遗传疾病的患者子集，使用一种可以调节过早无意义密码子处翻译终止过程的小分子药物进行治疗。在这里，我们回顾了翻译终止和 NMD，以及我们在过去 15 年中的后续努力，这些努力导致了ataluren 的鉴定、表征和临床测试，ataluren 是一种新型治疗药物，具有治疗由于无意义突变引起的广泛遗传疾病的潜力。
