PTC124 targets genetic disorders caused by nonsense mutations
PTC124 targets genetic disorders caused by nonsense mutations
复制标题
DOI：
10.1038/nature05756
复制
发表时间：
2007-05-03
期刊：
影响因子：
64.8
通讯作者：
Sweeney, H. Lee
中科院分区：
文献类型：
--
作者：
Welch, Ellen M.;Barton, Elisabeth R.;Sweeney, H. Lee
无义突变促进过早的翻译终止，并导致5 - 70%的大多数遗传性疾病(1)。对无义介导的囊性纤维化的研究表明，将特异性蛋白质合成从< 1%提高到正常水平的5%，可以大大降低疾病的严重程度或消除疾病的主要表现（2,3）。为了满足对一种能够抑制过早终止的药物的需求，我们鉴定了PTC124——一种新的化学实体，可以选择性地诱导核糖体读出过早终止密码子，而不是正常终止密码子。利用含无意义报告基因优化的PTC124活性，促进了人类和mdx小鼠原代肌细胞中表达肌营养不良蛋白无意义等位基因的肌营养不良蛋白的产生，并在药物暴露2 - 8周内恢复mdx小鼠的横切肌功能。PTC124在血浆暴露的动物中耐受性良好，远远超过无意义抑制所需的剂量。PTC124对过早终止密码子的选择性、其良好的活性谱、口服生物利用度和药理学特性表明，该药物可能具有广泛的临床潜力，可用于治疗大量有限或无治疗选择的遗传疾病。
Nonsense mutations promote premature translational termination and cause anywhere from 5 - 70% of the individual cases of most inherited diseases(1). Studies on nonsense-mediated cystic fibrosis have indicated that boosting specific protein synthesis from < 1% to as little as 5% of normal levels may greatly reduce the severity or eliminate the principal manifestations of disease(2,3). To address the need for a drug capable of suppressing premature termination, we identified PTC124 - a new chemical entity that selectively induces ribosomal readthrough of premature but not normal termination codons. PTC124 activity, optimized using nonsense-containing reporters, promoted dystrophin production in primary muscle cells from humans and mdx mice expressing dystrophin nonsense alleles, and rescued striated muscle function in mdx mice within 2 - 8 weeks of drug exposure. PTC124 was well tolerated in animals at plasma exposures substantially in excess of those required for nonsense suppression. The selectivity of PTC124 for premature termination codons, its well characterized activity profile, oral bioavailability and pharmacological properties indicate that this drug may have broad clinical potential for the treatment of a large group of genetic disorders with limited or no therapeutic options.