Effect of vanzacaftor/tezacaftor/ivacaftor on cystic fibrosis nasal epithelial cells and intestinal organoids compared to elexacaftor/tezacaftor/ivacaftor

Background The triple combination of vanzacaftor/tezacaftor/deutivacaftor (VAN/TEZ/D-IVA) is a new alternative to the established therapy with elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) in people with cystic fibrosis (pwCF). While both therapies show similar effects on lung function, VAN/TEZ/D-IVA further reduces sweat chloride concentrations. We aimed to explore the potential of triple combination VAN/TEZ/IVA to enhance the CFTR function in vitro. Methods Primary nasal epithelial cells (HNECs) and patient-derived intestinal organoids (PDIOs), both obtained from the same 12 F508del/F508del pwCF, were pretreated with ELX/TEZ, VAN/TEZ or left untreated. The response to the CFTR modulators was assessed using the transepithelial short-circuit current (I SC ) measured by the Ussing chamber method after the sequential addition of amiloride, forskolin (Fsk) with 3-isobutyl-1-methylxanthine (IBMX), IVA, CFTR inh -172 and ATP to HNECs from pwCF and 10 healthy donors (WT). ΔCFTR inh -172 I SC was used for assessment of CFTR activity (expressed as percentage of WT activity). The response of PDIOs to the CFTR modulators was tested using the forskolin induced swelling (FIS) assay. CFTR activity was expressed as area under the curve (AUC). Results Significant differences in CFTR-mediated chloride I SC were observed between untreated, ELX/TEZ-pretreated and VAN/TEZ-pretreated HNECs from pwCF. CFTR function was restored to 45% of WT levels with ELX/TEZ/IVA and to 67% with VAN/TEZ/IVA. Using the FIS assay, effects of both triple combinations on swelling of PDIOs were comparable. Conclusions VAN/TEZ/IVA demonstrated superior CFTR functional rescue in F508del/F508del HNECs than ELX/TEZ/IVA. These findings highlight the greater discriminatory power of airway epithelial electrophysiology compared to PDIOs when comparing highly effective CFTR modulator therapies.