Journal Article

CFTR Modulator Response in Nasal Organoids Derived from People with Cystic Fibrosis

Ceci, Aurora, Sorio, Claudio, Biffoni, Mauro, Lo Cicero, Stefania, Lucarelli, Marco, Cimino, Giuseppe, Spadaro, Francesca, Virgulti, Mariarita, Cerio, Anna Maria, Blaconà, Giovanna, Amato, Felice, Eramo, Adriana, Melotti, Paola, Allushi, Sara, Sette, Giovanni, Castelli, Germana

2025

Overview

Despite the progressive extension of variant eligibility to the triple combination of elexacaftor/tezacaftor/ivacaftor (ETI), most rare pathogenic variants remain ineligible for CFTR modulators. It is crucial to determine whether unexplored variants are rescuable by clinical modulators and to identify innovative therapeutic strategies for rescuing non-responder variants. The approach known as \"theratyping\" (in vitro testing of genotypes) has been accepted by the Food and Drug Administration (FDA) for the extension of clinical modulators' approval for in vitro responding genotypes. We used one of the most advanced models for theratyping: organoids derived from nasal epithelia of people with cystic fibrosis (pwCF). We optimized the forskolin-induced swelling (FIS) of organoids to assess CFTR basal or modulator-restored function. Nasal organoids mimicked the original epithelial tissue, CFTR residual activity, and modulator response. We set up the FIS assay using nasal organoids with reference genotypes and theratyped 38 rare (non-F508del) genotypes, either eligible or non-eligible for FDA approval, for treatment with ETI or ivacaftor. We found strong correspondence between the in vitro response of variants to modulators and their FDA approval status. Additionally, some previously uncharacterized variants have proven responsive to clinical modulators, with significant therapeutic implications. These results suggest that the nasal organoid FIS assay, pending confirmation of the prediction in the corresponding pwCF, might be considered as a powerful in vitro tool to predict modulator efficacy in each pwCF, guiding out-of-label prescription in CF, and to identify uncharacterized variants responsive to modulators. This approach may allow comparison of the efficacy of different therapeutics or the identification of innovative strategies for non-responding genotypes, improving personalized therapy and quality of life for pwCF.

• Publisher: MDPI AG
• Subject: airway organoids / airway stem cells / Aminophenols - pharmacology / Benzodioxoles - pharmacology / Cells / CFTR pathogenic variants / Clinical trials / Correspondence / Cystic fibrosis / Cystic Fibrosis - drug therapy / Cystic Fibrosis - genetics / Cystic Fibrosis - metabolism / Cystic Fibrosis - pathology / Cystic Fibrosis Transmembrane Conductance Regulator - genetics / Cystic Fibrosis Transmembrane Conductance Regulator - metabolism / disease modeling / FDA approval / Fibroblasts / Forskolin / Genotype / Genotypes / Humans / Indoles / Medical innovations / Mutation - genetics / Nasal Mucosa - drug effects / Nasal Mucosa - metabolism / Nasal Mucosa - pathology / Organoids / Organoids - drug effects / Organoids - metabolism / Organoids - pathology / Quality of life / Quinolones - pharmacology / targeted therapy