Cystic fibrosis (CF) is a life-shortening genetic disease caused by mutations of CFTR, the gene encoding cystic fibrosis transmembrane conductance regulator. Despite considerable progress in CF therapies, targeting specific CFTR genotypes based on small molecules has been hindered because of the substantial genetic heterogeneity of CFTR mutations in patients with CF, which is difficult to assess by animal models in vivo. There are broadly four classes (e.g., II, III, and IV) of CF genotypes that differentially respond to current CF drugs (e.g., VX-770 and VX-809). In this review, we shed light on the pharmacogenomics of diverse CFTR mutations and the emerging role of stem cell-based organoids in predicting the CF drug response. We discuss mechanisms that underlie differential CF drug responses both in organoid-based assays and in CF clinical trials, thereby facilitating the precision design of safer and more effective therapies for individual patients with CF.

中文翻译：

---

使用干细胞衍生的类器官对囊性纤维化CFTR变体的药理分析。

囊性纤维化（CF）是由CFTR突变引起的缩短寿命的遗传病，CFTR是编码囊性纤维化跨膜电导调节剂的基因。尽管CF疗法取得了长足的进步，但由于CF患者CFTR突变存在大量的遗传异质性，因此难以靶向以小分子为基础的特定CFTR基因型，这很难通过体内动物模型进行评估。CF基因型大致有四类（例如II，III和IV），它们对当前的CF药物（例如VX-770和VX-809）有不同的反应。在这篇综述中，我们阐明了各种CFTR突变的药物基因组学以及基于干细胞的类器官在预测CF药物反应中的新兴作用。