Pharmaceuticals Targeting Nonsense Mutations in Genetic Diseases Progress in Development
Pharmaceuticals Targeting Nonsense Mutations in Genetic Diseases Progress in Development
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DOI：
10.2165/00063030-200923030-00003
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发表时间：
2009-01-01
期刊：
影响因子：
6.8
通讯作者：
Clancy, John P.
中科院分区：
文献类型：
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作者：
Rowe, Steven M.;Clancy, John P.
过早终止密码子（PTC）是影响儿童和成人的多种遗传疾病的原因，并且是由在开放阅读框内产生异常终止密码子的碱基对取代产生的。几种核糖体结合药物，包括选择氨基糖苷类和合成的新型小分子，诱导PTC的“翻译通读”，在许多临床前和临床环境中恢复全长功能蛋白。在这篇综述中，我们研究了PTC抑制的机制基础，包括抑制PTC和真核细胞中转录水平的真核核糖体调节剂之间的相互作用的性质，以及抑制PTC的mRNA背景的重要性。我们还检查了临床前模型系统和临床试验（重点是PTC 124）中概念验证研究的结果。几项已发表的囊性纤维化研究报告了在短期评估期间囊性纤维化跨膜传导调节因子（CFTR）生物标志物的改善，包括局部和全身氨基糖苷类治疗以及口服PTC 124。这些结果，加上我们对翻译终止如何在PTC中调节的更好理解，将有助于指导未来涉及遗传疾病创新治疗策略的研究方向。
Premature termination codons (PTCs) are a cause of numerous genetic disorders spanning diseases that affect children and adults, and are produced by base pair substitutions that create abnormal stop codons within the open reading frame. Several ribosome-binding drugs, including select aminoglycosides and synthetic novel small molecules, induce' translational read through' of PTCs, restoring full-length functional protein in a number of preclinical and clinical settings. In this review, we examine the mechanistic underpinnings of PTC suppression, including the nature of the interactions between agents that suppress PTCs and the eukaryotic ribosome regulation of transcript levels in eukaryotic cells, and the importance of the mRNA context in suppression of PTCs. We also examine results from proof-of-concept studies in preclinical model systems and clinical trials (with a focus on PTC124). Several of the published studies in cystic fibrosis have reported improvements in cystic fibrosis transmembrane conductance regulator (CFTR) biomarkers during short-term evaluation, including topical and systemic aminoglycoside treatment, and oral dosing with PTC124. These results, coupled with our improved understanding of how translation termination is regulated at PTCs, will help guide future directions of research involving this innovative treatment strategy for genetic diseases.