PTC124 AS AN ORAL TREATMENT FOR NONSENSE-MUTATION-MEDIATED CYSTIC FIBROSIS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。PTC124是一种新型的口服生物可利用的小分子化合物，可促进含有过早停止密码子（也称为无义突变）的信使核糖核酸（mRNA）的核糖体读通。该药物有潜力克服无义突变患者的遗传缺陷，这是囊性纤维化（CF）和其他遗传疾病的基础。PTC124的开发为CF的治疗提供了一种独特的策略，将一种特定类型的遗传缺陷与一种小分子疗法结合起来进行测试，这种疗法有可能通过恢复缺失蛋白的产生来安全地纠正该遗传缺陷的表型表达。该方案描述了一项2a期、多位点、开放标签、剂量范围、疗效、安全性和药代动力学（PK）研究，研究对象为18至24名18岁的CF患者。该研究将作为整体开发计划的一部分进行，旨在获得监管部门批准PTC124用于治疗由囊性纤维化跨膜传导调节因子（CFTR）基因无意义突变引起的CF患者。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. PTC124 is a novel, orally bioavailable, small-molecule compound that promotes ribosomal readthrough of messenger ribonucleic acid (mRNA) containing a premature stop codon (also referred to as a nonsense mutation). The drug has the potential to overcome the genetic defect in patients with nonsense mutations as the basis for cystic fibrosis (CF) and other genetic disorders. Development of PTC124 offers a unique strategy for the treatment of CF, coupling testing for a specific type of genetic defect with a small-molecule remedy that has the potential to safely correct the phenotypic expression of that genetic defect by restoring the production of the missing protein. This protocol describes a Phase 2a, multi-site, open label, dose-ranging, efficacy, safety, and pharmacokinetic (PK) study in 18 to 24 CF patients 18 years of age. This study will be conducted as part of an overall development program aimed at obtaining regulatory approval of PTC124 as treatment for patients with CF resulting from a nonsense mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.