Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, Atlanta, Georgia.
Pediatr Pulmonol. 2019 Nov;54 Suppl 3(Suppl 3):S13-S17. doi: 10.1002/ppul.24547.
Small molecules that address fundamental defects underlying cystic fibrosis (CF), including modulators such as the approved drugs ivacaftor, lumacaftor, tezacaftor, and elexacaftor, have advanced dramatically over the past few years and are transforming care and prognosis among individuals with this disease. The new treatment strategies are predicated on established scientific insight concerning pathogenesis, and applying "personalized" or "precision" interventions for specific abnormalities of the cystic fibrosis transmembrane conductance regulator (CFTR). Even with the advent of highly effective triple drug combinations-which hold great promise for the majority of patients with CF worldwide-barriers to precision therapy remain. These include refractory CFTR variants (premature truncation codons, splice defects, large indels, severe missense mutations, and others) not addressed by available modulators, and access to leading-edge therapeutic compounds for patients with ultrarare forms of CF. In addition to describing the remarkable progress that has occurred regarding CF precision medicine, this review outlines some of the remaining challenges. The CF experience is emblematic of many conditions for which personalized interventions are actively being sought.
在过去的几年中，针对囊性纤维化（CF）根本缺陷的小分子药物取得了重大进展，包括已批准的药物 ivacaftor、lumacaftor、tezacaftor 和 elexacaftor 等调节剂，这些药物正在改变患有这种疾病的人群的治疗和预后。这些新的治疗策略基于对发病机制的既定科学认识，并针对囊性纤维化跨膜电导调节因子（CFTR）的特定异常应用“个性化”或“精准”干预措施。即使出现了高效的三联药物组合——这为全球大多数 CF 患者带来了巨大的希望——精准治疗仍然存在障碍。这些障碍包括现有调节剂无法解决的难治性 CFTR 变体（提前终止密码子、剪接缺陷、大片段缺失、严重错义突变等），以及为患有超罕见 CF 形式的患者提供前沿治疗化合物的途径。除了描述 CF 精准医学方面取得的显著进展外，本综述还概述了一些尚存的挑战。CF 的经验是许多正在积极寻求个性化干预措施的疾病的典型代表。
