Abstract
Highly effective CFTR modulator therapies have transformed the treatment of cystic fibrosis (CF). Elexacaftor/tezacaftor/ivacaftor (ETI) leads to restoration of CFTR-mediated chloride transport of around 40% of normal CFTR activity and results in substantial clinical benefits in people with CF and at least one F508del allele. Interestingly, people carrying the complex allele L467F;F508del do not show clinical improvements following initiation of ETI. However, the effects of the novel triple combination vanzacaftor/tezacaftor/deutivacaftor (VTD) on this complex allele are unknown. In this study, we compared the effects of ETI and VTD on CFTR function in highly differentiated primary human nasal epithelial cultures (pHNECs) derived from 7 people with CF carrying at least one L467F;F508del complex allele and 9 healthy controls. CFTR-mediated chloride transport was quantified by transepithelial short-circuit current measurements in Ussing chambers following treatment with ETI, VTD, or vehicle control. Treatment with ETI showed a numerical but not statistically significant improvement in CFTR-mediated chloride currents in pHNECs carrying the L467F;F508del complex allele. In contrast, VTD significantly increased forskolin/IBMX-stimulated currents (p < 0.001), forskolin/IBMX plus deutivacaftor-stimulated currents (p < 0.01) and CFTRinhibitor-172-inhibited currents (p < 0.001) compared to vehicle control. The mean increase in forskolin/IBMX plus deutivacaftor-stimulated current corresponded to about 10% of CFTR-mediated currents in healthy cultures. In exploratory subgroup analyses, VTD-mediated CFTR rescue was more pronounced in L467F;F508del-homozygous than in compound heterozygous cultures. In conclusion, our results demonstrate that VTD partially restores CFTR function in epithelial cultures carrying the L467F;F508del complex allele. These findings provide a rationale for further clinical evaluation of VTD in people with CF carrying L467F;F508del and potentially other complex CFTR alleles that do not respond to ETI.