Department of Genetics, The Life Sciences Institute, The Hebrew University, Jerusalem, Israel; SpliSense Therapeutics, Givat Ram Campus, Hebrew University, Jerusalem, Israel.
INSERM U 1151, Institut Necker Enfants Malades, Paris, France; Université Paris Sorbonne, France.
Curr Opin Pharmacol. 2017 Jun;34:125-131. doi: 10.1016/j.coph.2017.09.017. Epub 2017 Nov 10.
Premature termination codons (PTC) originate from nucleotide substitution introducing an in-frame PTC. They induce truncated, usually non-functional, proteins, degradation of the PTC containing transcripts by the nonsense-mediated decay (NMD) pathway and abnormal exon skipping. Readthrough compounds facilitate near cognate amino-acyl-tRNA incorporation, leading potentially to restoration of a functional full-length protein. Splicing mutations can lead to aberrantly spliced transcripts by creating a cryptic splice site or destroying a normal site. Most mutations result in disruption of the open reading frame and activation of NMD. Antisense oligonucleotides are single stranded short synthetic RNA-like molecules chemically modified to improve their stability and ability to recognize their target RNAs and modify the splice site. This review focuses on recent developments in therapies aiming to improve the health of CF patients carrying nonsense or splicing mutations.
提前终止密码子（PTC）源于核苷酸替换，引入无义 PTC。它们诱导截短的、通常无功能的蛋白质，通过无义介导的衰变（NMD）途径降解包含 PTC 的转录本，并导致异常外显子跳跃。通读化合物促进近乎同源的氨酰-tRNA 掺入，从而有可能恢复有功能的全长蛋白质。剪接突变通过创建隐秘剪接位点或破坏正常位点导致异常剪接的转录本。大多数突变导致开放阅读框的破坏和 NMD 的激活。反义寡核苷酸是经过化学修饰以提高其稳定性和识别其靶 RNA 并修饰剪接位点的单链短合成 RNA 样分子。这篇综述重点介绍了旨在改善携带无义或剪接突变的 CF 患者健康的治疗方法的最新进展。
