Superior efficacy of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) over tezacaftor/ivacaftor (TEZ/IVA) in people with cystic fibrosis (CF) and Phe508del/Phe508del genotype was shown in clinical trials. We utilized intestinal organoid approach to compare in vitro responses to these 2 CFTR modulator drug combinations and to check potential inter-individual variability in therapeutic response to the triple combination. Organoids from 17 subjects with Phe508del/Phe508del were screened with forskolin induced swelling assay. Significantly larger swelling, when exposed to ELX/TEZ/IVA as compared to TEZ/IVA, was observed in 16 of them. However, 1 sample showed no additional effect of ELX. The finding of unique CFTR variants in this sample indicates that genetic traits other than CF-causing CFTR mutation are worth exploring as they may have an impact on the definitive modulator drug response.

elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) 在囊性纤维化 (CF) 和 Phe508del/Phe508del 基因型患者中的疗效优于 tezacaftor/ivacaftor (TEZ/IVA)。我们利用肠道类器官方法进行体外比较对这 2 种 CFTR 调节剂药物组合的反应，并检查对三联组合的治疗反应的潜在个体间变异性。用毛喉素诱导肿胀试验筛选来自 17 名 Phe508del/Phe508del 受试者的类器官。与 TEZ/IVA 相比，当暴露于 ELX/TEZ/IVA 时，在其中 16 个中观察到明显更大的肿胀。然而，1 个样品没有显示 ELX 的额外作用。在该样本中发现独特的 CFTR 变体表明，除了导致 CF 的 CFTR 突变之外的遗传特征值得探索，因为它们可能对最终的调节剂药物反应产生影响。