vanzacaftor/tezacaftor/ivacaftor对囊性纤维化气道上皮细胞的影响

IF 5.4 2区医学 Q1 RESPIRATORY SYSTEM

Journal of Cystic Fibrosis Pub Date : 2025-06-01 DOI:10.1016/j.jcf.2025.03.574

L. Borek Dohalska , S. Novotna , E. Furstova , Z. Varenyiova , M. Modrak , T. Dousova , P. Drevinek

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引用次数: 0

摘要

目的最新的由vanzacaftor (V)、tezacaftor (T)和deutivacaftor (D)组成的三组分CFTR调节药物，正在成为囊性纤维化（pwCF）患者现有的elexaftor (E)、tezacaftor (T)和ivacaftor (I)联合治疗的新选择。虽然临床试验数据显示，与ETI相比，VTD对FEV1%的影响相当，但在改善汗液氯化物浓度方面的优势被报道。因此，我们的研究目的是通过测量短路电流（ISC）来研究vanzacaftor进一步改善CFTR功能的潜力。方法采用Ussing法对12株F508del/F508del pwCF的人鼻上皮细胞（HNEC）进行分析。实验前48小时用CFTR调制剂（3 μM E+3 μM T，或3 μM V+3 μM T）处理或预处理HNEC。依次加入100 μM amiloride、10 μM forskolin （Fsk）和100 μM 3-异丁基-1-甲基黄嘌呤（IBMX）、10 μM I、10 μM CFTRinhibitor-172 （CFTRinh172）和100 μM ATP后测定ISC。CFTR活性计算为ΔFsk/IBMX+I ISC和ΔCFTRinh172 ISC。自发CFTR活性测定为添加amiloride后的ISC与添加CFTRinh172后的ISC的差异。结果isc测量显示VTI治疗后CFTR功能显著改善。与ETI相比，VTI显著增加了ΔFsk/IBMX ISC(差异：5.36 μA/cm2, p <；0.001)，并显著增加ΔCFTRinh 172 ISC(差异：9.84 μA/cm²，p <；0.001)。此外，vt处理的自发CFTR活性比et处理的培养物提高了6.27 μA/cm2 (p <；0.001)。结论与ETI相比，VTI治疗F508del/F508del HNEC的CFTR功能恢复明显更好。这些结果与临床试验中看到的汗液氯化物值的改善是一致的。捷克共和国卫生部资助，批准号NU23-07-00079。

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WS14.05Effect of vanzacaftor/tezacaftor/ivacaftor on cystic fibrosis airway epithelial cells

Objectives

The latest triple-component CFTR modulator drug, consisting of vanzacaftor (V), tezacaftor (T) and deutivacaftor (D), is becoming a new treatment alternative to the established combination of elexacaftor (E), tezacaftor (T) and ivacaftor (I) in people with cystic fibrosis (pwCF). While the clinical trial data showed a comparable effect of VTD on FEV1% when compared to ETI, the superiority was reported in terms of improvement of sweat chloride concentrations. Therefore, the aim of our study was to investigate the potential of vanzacaftor to further improve CFTR function by measuring short-circuit current (I_SC).

Methods

Primary human nasal epithelial cells (HNEC) derived from 12 F508del/F508del pwCF were analysed in Ussing chamber. HNEC were untreated or pretreated with CFTR modulators (either 3 μM E+3 μM T, or 3 μM V+3 μM T) 48 hours prior Ussing experiments. I_SC was measured after sequential addition of 100 μM amiloride, 10 μM forskolin (Fsk) and 100 μM 3-isobutyl-1-methylxanthine (IBMX), 10 μM I, 10 μM CFTRinhibitor-172 (CFTRinh172) and 100 μM ATP. CFTR activity was calculated as ΔFsk/IBMX+I I_SC and ΔCFTRinh172 I_SC. Spontaneous CFTR activity was determined as difference between I_SC after addition of amiloride and I_SC after addition of CFTRinh172.

Results

I_SC measurements demonstrate significant CFTR function improvement after VTI treatment. Compared to ETI, VTI showed significant increase of ΔFsk/IBMX I_SC (difference: 5.36 μA/cm², p < 0.001) as well as significant increase of ΔCFTRinh 172 I_SC (difference: 9.84 μA/cm², p < 0.001). Moreover, spontaneous CFTR activity was improved in VT-treated over ET-treated cultures by 6.27 μA/cm² (p < 0.001).

Conclusions

Our results show significantly greater restoration of CFTR function in F508del/F508del HNEC treated with VTI compared to ETI. These results are in line with the improved sweat chloride values seen in the clinical trial.

Supported by Ministry of Health of the Czech Republic, grant no NU23-07-00079.

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来源期刊

Journal of Cystic Fibrosis 医学-呼吸系统

CiteScore

10.10

自引率

13.50%

发文量

1361

审稿时长

50 days

期刊介绍： The Journal of Cystic Fibrosis is the official journal of the European Cystic Fibrosis Society. The journal is devoted to promoting the research and treatment of cystic fibrosis. To this end the journal publishes original scientific articles, editorials, case reports, short communications and other information relevant to cystic fibrosis. The journal also publishes news and articles concerning the activities and policies of the ECFS as well as those of other societies related the ECFS.