A functional comparison of vanzacaftor/tezacaftor/deutivacaftor and elexacaftor/tezacaftor/ivacaftor in patient-derived intestinal organoids with rare CFTR variants.

BACKGROUND

Cystic fibrosis (CF) results from pathogenic CFTR variants that impair epithelial chloride and bicarbonate transport. CFTR modulators such as elexacaftor/tezacaftor/ivacaftor (ETI) have transformed CF care, and the next-generation regimen vanzacaftor/tezacaftor/deutivacaftor (VTD) has recently been introduced on the market. VTD offers once-daily dosing and expanded regulatory approval, yet its functional advantages remain not fully characterized across a broad set of genotypes. Consequently, we set out to compare CFTR functional rescue of ETI and VTD in primary patient-derived intestinal organoids (PDIOs) harbouring a broad range of CFTR variants.

METHODS

We evaluated ETI and VTD efficacy in 62 PDIO lines representing 42 rare CFTR genotypes and reference groups (p.Phe508del/p.Phe508del, p.Phe508del/class I, class I/class I). CFTR rescue was assessed by CFTR function by steady-state lumen area quantification and forskolin-induced swelling assays and CFTR maturation via western blot.

RESULTS

Across rare variants, CFTR functional rescue by ETI and VTD strongly correlated, with modest but consistent VTD advantages in a subset of folding-defective genotypes (e.g., p.Val520Phe). Three PDIOs showed disproportionately high responses to VTD. VTD increased CFTR maturation more effectively than ETI, yet demonstrated similar acute effects on CFTR function.

CONCLUSIONS

VTD provides modest genotype-specific functional advantages and enhanced CFTR maturation but is largely comparable to ETI across rare variants. PDIO-based screenings performed in this study underline again their potential for theratyping, which is particularly critical for guiding decisions on accessibility for rare variants in an era with a variety of modulators, and combinations thereof.