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

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

  • J Cyst Fibros. 2026 Jun 16:S1569-1993(26)01643-7. doi: 10.1016/j.jcf.2026.06.002.
Suzanne Kroes 1,  Lara Zaidi 1,  Heleen N Sonneveld-van Kooten 1,  Lianne Winkel 1,  Kris De Boeck 2,  Margarida Amaral 3,  Cornelis K van der Ent 4,  Jeffrey M Beekman 1,  Sacha Spelier 5,  HIT-CF Organoid Study group
Affiliations

Affiliations

  • 1 Regenerative Medicine Utrecht, University Medical Center, Utrecht University, 3584 CT, Utrecht, the Netherlands.
  • 2 Department of Development and Regeneration, Woman and Child Unit, CF Research Lab, KU Leuven, Leuven, Belgium; Department of Pediatrics, Pediatric Pulmonology, University Hospital Leuven, Leuven, Belgium.
  • 3 BioISI-Biosystems Integrative Sciences Institute, Faculty of Sciences, University of Lisboa, Campo Grande, 1749-016, Lisboa, Portugal.
  • 4 Department of Pediatric Respiratory Medicine, Wilhelmina Children's Hospital, University Medical Center, Utrecht University, 3584 EA, Utrecht, the Netherlands.
  • 5 Regenerative Medicine Utrecht, University Medical Center, Utrecht University, 3584 CT, Utrecht, the Netherlands. Electronic address: [email protected].
PMID: 42303492 DOI: 10.1016/j.jcf.2026.06.002
Abstract

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.

Keywords

Alyftrek; CFTR modulator therapies; Cystic fibrosis; Forskolin-induced swelling assay; Patient-derived intestinal organoids; Rare genotypes; Trikafta.

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