Nonsense mutations, often resulting from single-nucleotide substitutions, produce mRNA harboring a premature termination codon (PTC), which causes the premature termination of protein synthesis. This produces truncated and non-functional proteins, which cause different genetic diseases, including cystic fibrosis (CF). This work aims to investigate the ability of NV848 (N-(5-methyl-1,2,4-oxadiazol-3-yl)acetamide), a translational readthrough-inducing drug (TRID), to rescue CF transmembrane conductance regulator (CFTR) protein expression in a murine model characterized by the G542X nonsense mutation in the CFTR gene. In vitro experiments assessed the drug’s stability in human hepatic metabolism, and in vivo investigations on wild-type mice allowed us to clarify the distribution of the drug to the target organs. Moreover, its efficacy in recovering the CFTR protein after chronic treatment was assessed in G542X homozygous mice. Our results provide valuable insights into the biodistribution and therapeutic attributes of NV848, representing a promising therapeutic tool for enhanced clinical outcomes in individuals affected by CF with nonsense mutations.

中文翻译：

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促进 CF 小鼠模型中无义突变的读通：NV848 在挽救 CFTR 蛋白表达中的生物分布和疗效


无义突变通常由单核苷酸取代引起，产生携带过早终止密码子 （PTC） 的 mRNA，这会导致蛋白质合成过早终止。这会产生截短和非功能性蛋白质，从而导致不同的遗传疾病，包括囊性纤维化 （CF）。本研究旨在研究翻译通读诱导药物 （TRID） NV848 （N-（5-methyl-1,2,4-oxadiazol-3-yl）acetamide） 在以 CFTR 基因 G542X 无义突变为特征的小鼠模型中挽救 CF 跨膜传导调节因子 （CFTR） 蛋白表达的能力。体外 实验评估了药物在人肝代谢中的稳定性， 对野生型小鼠的体内研究使我们能够阐明药物在靶器官中的分布。此外，在 G542X 纯合子小鼠中评估了其在慢性治疗后恢复 CFTR 蛋白的疗效。我们的结果为 NV848 的生物分布和治疗特性提供了有价值的见解，代表了一种有前途的治疗工具，可改善具有无义突变的 CF 患者患者的临床结果。