Zainal Abidin Noreen, Haq Iram J, Gardner Aaron I, Brodlie Malcolm
a Paediatric Respiratory Medicine , Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust , Newcastle upon Tyne , UK.
b Institute of Cellular Medicine , Newcastle University , Newcastle upon Tyne , UK.
Expert Opin Pharmacother. 2017 Sep;18(13):1363-1371. doi: 10.1080/14656566.2017.1359255. Epub 2017 Aug 1.
Cystic fibrosis (CF) is one of the most common genetically-acquired life-limiting conditions worldwide. The underlying defect is dysfunction of the cystic fibrosis transmembrane-conductance regulator (CFTR) which leads to progressive lung disease and other multi-system effects. Around 10% of people with CF have a class I nonsense mutation that leads to production of shortened CFTR due to a premature termination codon (PTC). Areas covered: We discuss the discovery of the small-molecule drug ataluren, which in vitro has been shown to allow read-through of PTCs and facilitate synthesis of full-length protein. We review clinical studies that have been performed involving ataluren in CF. Early-phase short-term cross-over studies showed improvement in nasal potential difference. A follow-up phase III randomised controlled trial did not show a significant difference for the primary outcome of lung function, however a post-hoc analysis suggested possible benefit in patients not receiving tobramycin. A further randomised controlled trial in patients not receiving tobramycin has been reported as showing no benefit but has not yet been published in full peer-reviewed form. Expert opinion: A small-molecule approach to facilitate read-through of PTCs in nonsense mutations makes intuitive sense. However, at present there is no high-quality evidence of clinical efficacy for ataluren in people with CF.
囊性纤维化(CF)是全球最常见的遗传性、危及生命的疾病之一。其根本缺陷是囊性纤维化跨膜传导调节因子(CFTR)功能障碍,这会导致进行性肺部疾病和其他多系统影响。约10%的CF患者存在I类无义突变,由于过早出现终止密码子(PTC),导致产生缩短的CFTR。涵盖领域:我们讨论了小分子药物阿他芦醇的发现,该药物在体外已被证明可使PTC通读并促进全长蛋白的合成。我们回顾了涉及阿他芦醇治疗CF的临床研究。早期短期交叉研究显示鼻电位差有所改善。一项后续的III期随机对照试验并未显示肺功能主要结局有显著差异,然而事后分析表明在未接受妥布霉素治疗的患者中可能有益。另一项针对未接受妥布霉素治疗患者的随机对照试验报告称未显示出益处,但尚未以完整的同行评审形式发表。专家意见:促进无义突变中PTC通读的小分子方法具有直观意义。然而,目前尚无高质量证据表明阿他芦醇对CF患者具有临床疗效。