Correlation between patient-derived intestinal organoids and clinical responses to CFTR modulators in people with cystic fibrosis homozygous for F508del

Abstract

Background: Patient-derived intestinal organoids (PDIOs) are an in vitro tool used to predict clinical responses to CFTR modulators in people with cystic fibrosis (pwCF). Although strong genotype-based correlations have been observed, individual responses among F508del homozygous pwCF remain variable. We aimed to assess this correlation specifically within this group.

Methods: A retrospective multi-center study included 60 F508del homozygous pwCF from six Belgian CF centers. The 15 highest and 15 lowest PDIO responders to tezacaftor/ivacaftor (TI) and elexacaftor/tezacaftor/ivacaftor (ETI) were selected based on Forskolin-induced swelling (FIS) assay results. Clinical outcomes-sweat chloride concentration (SCC), spirometry, BMI, pulmonary exacerbations, and IV antibiotic use-were measured before and after treatment. Additionally, transcriptomics and 13 CFTR SNPs were compared between high and low responders to TI to assess whether variants within CFTR contribute to phenotypic variability.

Results: Baseline characteristics were similar between low and high PDIO responders, except for lower pre-treatment SCC in high TI responders. No significant differences in clinical outcomes were observed between groups after treatment. PDIO responses were higher with ETI than TI (p < 0.001). PDIO response magnitude was significantly associated with changes in SCC and ppFEV1 (p < 0.001). No differences in SNPs or transcriptomics were found.

Conclusion: While high and low PDIO response groups did not differ in clinical outcomes individually, PDIO response magnitude was significantly associated with SCC and ppFEV1 changes when TI and ETI data were combined, suggesting its potential as a biomarker for modulator treatment efficacy.

Keywords: CFTR functional assays; Cystic fibrosis; F508del; Patient derived intestinal organoids.