促进囊性纤维化小鼠模型中无义突变的转化通路:评估 NV848 1,2,4-恶二唑化合物在挽救 CFTR 蛋白表达方面的生物分布和疗效。

IF 12.1 1区 医学 Q1 BIOTECHNOLOGY & APPLIED MICROBIOLOGY
Molecular Therapy Pub Date : 2024-12-04 Epub Date: 2024-10-28 DOI:10.1016/j.ymthe.2024.10.028
Ignazio Fiduccia, Federica Corrao, Maria Grazia Zizzo, Riccardo Perriera, Francesco Genovese, Emanuele Vitale, Davide Ricci, Raffaella Melfi, Marco Tutone, Andrea Pace, Laura Lentini, Ivana Pibiri
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引用次数: 0

摘要

无义突变通常由单核苷酸置换引起,产生的 mRNA 含有过早终止密码子(PTC),导致蛋白质合成过早终止。这会产生截短和无功能的蛋白质,导致不同的遗传疾病,包括囊性纤维化(CF)。这项研究旨在探讨 NV848(N-(5-甲基-1,2,4-恶二唑-3-基)乙酰胺)(一种翻译突破诱导药物(TRID))在以 CFTR 基因 G542X 无义突变为特征的小鼠模型中挽救囊性纤维化跨膜传导调节器(CFTR)蛋白表达的能力。体外实验评估了药物在人体肝脏代谢中的稳定性,而对野生型小鼠的体内研究则明确了药物在靶器官中的分布。此外,我们还在 G542X 基因同型小鼠体内评估了该药物在慢性治疗后恢复 CFTR 蛋白的功效。我们的研究结果为了解 NV848 的生物分布和治疗特性提供了有价值的见解,为提高无义突变 CF 患者的临床疗效提供了有希望的治疗工具。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Promoting readthrough of nonsense mutations in CF mouse model: Biodistribution and efficacy of NV848 in rescuing CFTR protein expression.

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.

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来源期刊
Molecular Therapy
Molecular Therapy 医学-生物工程与应用微生物
CiteScore
19.20
自引率
3.20%
发文量
357
审稿时长
3 months
期刊介绍: Molecular Therapy is the leading journal for research in gene transfer, vector development, stem cell manipulation, and therapeutic interventions. It covers a broad spectrum of topics including genetic and acquired disease correction, vaccine development, pre-clinical validation, safety/efficacy studies, and clinical trials. With a focus on advancing genetics, medicine, and biotechnology, Molecular Therapy publishes peer-reviewed research, reviews, and commentaries to showcase the latest advancements in the field. With an impressive impact factor of 12.4 in 2022, it continues to attract top-tier contributions.
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