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首页> 美国卫生研究院文献>Proceedings of the National Academy of Sciences of the United States of America >PTC124 is an orally bioavailable compound that promotes suppression of the human CFTR-G542X nonsense allele in a CF mouse model
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PTC124 is an orally bioavailable compound that promotes suppression of the human CFTR-G542X nonsense allele in a CF mouse model

机译：PTC124是一种口服生物利用化合物可促进CF小鼠模型中人CFTR-G542X无效等位基因的抑制

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摘要

Nonsense mutations inactivate gene function and are the underlying cause of a large percentage of the individual cases of many genetic disorders. PTC124 is an orally bioavailable compound that promotes readthrough of premature translation termination codons, suggesting that it may have the potential to treat genetic diseases caused by nonsense mutations. Using a mouse model for cystic fibrosis (CF), we show that s.c. injection or oral administration of PTC124 to Cftr−/− mice expressing a human CFTR-G542X transgene suppressed the G542X nonsense mutation and restored a significant amount of human (h)CFTR protein and function. Translational readthrough of the premature stop codon was demonstrated in this mouse model in two ways. First, immunofluorescence staining showed that PTC124 treatment resulted in the appearance of hCFTR protein at the apical surface of intestinal glands in Cftr−/− hCFTR-G542X mice. In addition, functional assays demonstrated that PTC124 treatment restored 24–29% of the average cAMP-stimulated transepithelial chloride currents observed in wild-type mice. These results indicate that PTC124 can effectively suppress the hCFTR-G542X nonsense mutation in vivo. In light of its oral bioavailability, safety toxicology profile in animal studies, and efficacy with other nonsense alleles, PTC124 has the potential to be an important therapeutic agent for the treatment of inherited diseases caused by nonsense mutations.
机译：无意义的突变使基因功能失活，并且是许多遗传性疾病个体病例中很大一部分的根本原因。 PTC124是一种口服生物可利用的化合物，可促进过早翻译终止密码子的通读，表明它可能具有治疗由无意义突变引起的遗传疾病的潜力。使用用于囊性纤维化（CF）的小鼠模型，我们可以看到向表达人CFTR-G542X转基因的Cftr-/-小鼠注射或口服PTC124可抑制G542X的无意义突变，并恢复了大量的人（h）CFTR蛋白和功能。在这种小鼠模型中以两种方式证明了过早终止密码子的翻译通读。首先，免疫荧光染色显示PTC124处理导致Cftr-/-hCFTR-G542X小鼠的小肠顶表面出现hCFTR蛋白。此外，功能分析表明，PTC124处理可恢复野生型小鼠中观察到的平均cAMP刺激的经上皮氯化物电流的24–29％。这些结果表明PTC124可以在体内有效地抑制hCFTR-G542X无义突变。鉴于其口服生物利用度，在动物研究中的安全毒理学特征以及与其他无意义等位基因的功效，PTC124有潜力成为治疗由无意义突变引起的遗传性疾病的重要治疗剂。

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