PTC

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 PTC124是一种小分子化合物，可以促进信使核糖核酸的核糖体阅读，其中包含一种称为无义突变的提前终止密码子。这种药物有可能克服无义突变患者的基因缺陷，这种缺陷是囊性纤维化和其他遗传性疾病的基础。这项2a期多点、开放标记、剂量范围、有效性、安全性和PK研究将在18岁或18岁以上的无义突变介导的CF患者中进行。患者将接受连续递增剂量的PTC124(每天3次)，在第1周期中剂量为4、4和8 mg/kg，在第2周期中为10、10和20 mg/kg。该药物将分两个重复的28天周期给药，包括14天的治疗和14天的停药。 PTC124的开发为囊性纤维化的治疗提供了一种独特的策略，将对特定类型的遗传缺陷的检测与一种小分子药物相结合，这种药物有可能通过恢复缺失蛋白质的生产来安全地纠正该遗传缺陷的表型表达。 这项研究的主要目的是记录药物动力学活性，通过鼻腔跨上皮电位差(TEPD)的变化来确定，给药方案可以安全地给药。该方案将评估其他药理活性的测量，评估药物依从性，并评估PTC124的安全性和对CF患者的PK。

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 small-molecule compound that promotes ribosomal read-through of messenger ribonucleic acid containing a premature stop codon 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 and other genetic disorders. This Phase 2a-multisite, open-label, dose-ranging, efficacy, safety, and PK study will be performed in 18 patients with nonsense-mutation-mediated CF who are 18 years old or older. Patients will receive sequential, escalating dose levels of PTC124 (given 3 times per day) at doses of 4-,4 -, and 8 -mg/kg in cycle 1 and 10, 10 and 20 mg/kg in Cycle 2. The drug will be given in 2 repeated 28-day cycles comprising 14 days on therapy and 14 days off therapy. Development of PTC124 offers a unique strategy for the treatment of cystic fibrosis, 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. The primary objective of this study is to document pharmacodynarnic activity as determined by changes in the nasal transepithelial potential difference (TEPD) with a dosing regimen that can be safely administered. The protocol will assess other measures of pharmacological activity, evaluated drug compliance, and evaluated PTC124 safety and PK in patients with CF.