囊性纤维化基因治疗

Cystic fibrosis gene therapy

囊性纤维化(cystic fibrosis,CF)是由编码cAMP调控阴离子通道的囊性纤维化跨膜电导调节剂(cystic fibrosis transmembrane conductance regulator,CFTR)基因突变引起的常染色体隐性遗传病。CF虽然是一种多器官系统疾病,但大多数CF患者死于继发的肺部疾病,大多在儿童期发病,以慢性细菌感染和炎症为特征。近90%的CF患者至少有一个ΔF508基因拷贝突变,如果有数百个CFTR突变会导致一系列严重的疾病。无论何种致病突变,CFTR基因替代方法都是有效的。从1989年发现CFTR基因后,CF基因治疗的体外试验在1990年迅速开展。从1993年开始许多基因治疗的临床试验开始尝试修复气道上皮细胞CFTR缺陷。尽管学者们热情很高,但FDA还没有批准CF基因治疗。该综述主要讨论CF基因治疗的发展史,从CFTR发现基因到目前最先进的载体设计。虽然CF基因治疗的实施比最初设想的更具挑战性,但由于不断的创新,未来有可能成为现实。

Cystic fibrosis(CF)is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator(CFTR)gene that encodes a cAMP-regulated anion channel.Although CF is a multi-organ system disease,most people with CF die of progressive lung disease that begins early in childhood and is characterized by chronic bacterial infection and inflammation.Nearly 90%of people with CF have at least one copy of theΔF508 mutation,but there are hundreds of CFTR mutations that result in a range of disease severities.A CFTR gene replacement approach would be efficacious regardless of the disease-causing mutation.After the discovery of the CFTR gene in 1989,the in vitro proof-of-concept for gene therapy for CF was quickly established in 1990.In 1993,the first of many gene therapy clinical trials attempted to rescue the CF defect in airway epithelia.Despite the initial enthusiasm,there is still no FDA-approved gene therapy for CF.Here we discuss the history of CF gene therapy,from the discovery of the CFTR gene to current state-of-the-art gene delivery vector designs.While implementation of CF gene therapy has proven more challenging than initially envisioned;thanks to continued innovation,it may yet become a reality.