囊性纤维化（CF）由囊性纤维化跨膜电导调节因子（CFTR）基因的缺陷引起。CFTR调节药物可能能够克服特定的缺陷，例如Trikafta，它是Elexacaftor、Tezacaftor和Ivacaftor（ETI）的临床批准三联合剂，可以有效修复最常见的F508del致病突变体的功能，即使是单拷贝突变等位基因型也能有效。然而，大多数缺乏F508del等位基因的罕见基因型仍然不符合目标治疗的条件。通过使用在体外模拟患者疾病的鼻腔条件重编程细胞（CRC）细胞模型的创新方法，这些细胞模型由于细胞培养建立的100％效率而可从每位患者身上获得，我们对孤儿CFTR突变L1077P进行了治疗研究。蛋白质研究、促进福尔司琴诱导的器官样体胀和Ussing室分析一致地证明了ETI能够挽救L1077P变体的功能。值得注意的是，即使在单拷贝L1077P等位基因的背景下，这种挽救也可以发生，并且似乎能增强其表达。因此，罕见基因型的单等位基因治疗的可能性也出现在机制的一部分，即等位基因特异性调节。值得注意的是，除了提供关于特定CFTR致病变体或基因型的药物疗效的指示外，这种方法还允许在其遗传背景中评估单个患者细胞的响应。从这个角度来看，我们的研究支持体外引导的个体化CF治疗，也适用于几乎被排除在临床试验之外的罕见患者。©2023 BioMed Central有限公司，Springer Nature的一部分。

Cystic fibrosis (CF) is caused by defects of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR-modulating drugs may overcome specific defects, such as the case of Trikafta, which is a clinically approved triple combination of Elexacaftor, Tezacaftor and Ivacaftor (ETI) that exhibited a strong ability to rescue the function of the most frequent F508del pathogenic variant even in genotypes with the mutated allele in single copy. Nevertheless, most rare genotypes lacking the F508del allele are still not eligible for targeted therapies. Via the innovative approach of using nasal conditionally reprogrammed cell (CRC) cell-based models that mimic patient disease in vitro, which are obtainable from each patient due to the 100% efficiency of the cell culture establishment, we theratyped orphan CFTR mutation L1077P. Protein studies, Forskolin-induced organoid swelling, and Ussing chamber assays congruently proved the L1077P variant function rescue by ETI. Notably, this rescue takes place even in the context of a single-copy L1077P allele, which appears to enhance its expression. Thus, the possibility of single-allele treatment also arises for rare genotypes, with an allele-specific modulation as part of the mechanism. Of note, besides providing indication of drug efficacy with respect to specific CFTR pathogenic variants or genotypes, this approach allows the evaluation of the response of single-patient cells within their genetic background. In this view, our studies support in vitro guided personalized CF therapies also for rare patients who are nearly excluded from clinical trials.© 2023. BioMed Central Ltd., part of Springer Nature.