Cystic fibrosis (CF) is a genetic disease caused by mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene. Although CF is a multiorgan disease, the leading causes of morbidity and mortality are related to progressive lung disease. Current understanding of the effects of the broad spectrum of CFTR mutations on CFTR function has allowed for the development of CFTR modulator therapies. Despite the remarkable impact that these therapies have had, there remains a significant proportion of people with CF (estimated at 10-15% of the global CF population) who are genetically ineligible for, or intolerant of, current CFTR-targeting therapies and whose therapeutic needs remain unmet. Inhaled genetic therapies offer the prospect of addressing the unmet pulmonary treatment need in people with CF, with several approaches, including gene addition therapy (the focus of this review), RNA-based therapies, antisense oligonucleotides, and gene editing, being explored. Various nonviral and viral vectors have been investigated for CF gene addition therapy for mutation-agnostic restoration of CFTR function in the lungs. Lentiviral vectors offer the prospect of highly efficient and long-lasting gene expression, and the potential to be safely and, in contrast to other commonly used viral vectors, effectively redosed. A third-generation lentiviral vector pseudotyped with Sendai virus F and HN envelope proteins (rSIV.F/HN) has been developed for the treatment of CF. Promising preclinical results support the progression of this vector carrying a full-length CFTR transgene (BI 3720931) into a first-in-human clinical trial expected to begin in 2024.

中文翻译：

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囊性纤维化的慢病毒基因疗法：一种很有前途的方法和首次人体试验。


囊性纤维化 （CF） 是由 CFTR（囊性纤维化跨膜传导调节因子）基因突变引起的遗传性疾病。尽管 CF 是一种多器官疾病，但发病率和死亡率的主要原因与进行性肺病有关。目前对广谱 CFTR 突变对 CFTR 功能影响的理解使 CFTR 调节剂疗法的发展成为可能。尽管这些疗法产生了显着影响，但仍有很大一部分 CF 患者（估计占全球 CF 人口的 10-15%）在遗传上不符合或不耐受当前的 CFTR 靶向疗法，并且其治疗需求仍未得到满足。吸入基因疗法为解决 CF 患者未满足的肺部治疗需求提供了前景，正在探索多种方法，包括基因添加疗法（本综述的重点）、基于 RNA 的疗法、反义寡核苷酸和基因编辑。已经研究了各种非病毒和病毒载体用于 CF 基因添加疗法，用于肺部 CFTR 功能的突变不可知性恢复。慢病毒载体具有高效和持久的基因表达前景，并且与其他常用的病毒载体相比，具有安全且有效重新给药的潜力。已经开发了使用仙台病毒 F 和 HN 包膜蛋白 （rSIV.F/HN） 进行假型的第三代慢病毒载体，用于治疗 CF。有希望的临床前结果支持该载体携带全长 CFTR 转基因 （BI 3720931） 进入首次人体临床试验，预计将于 2024 年开始。