Systemic effects of cystic fibrosis transmembrane conductance regulator (CFTR) modulators on the plasma and serum proteome

ABSTRACT: Cystic fibrosis (CF), resulting from a dysfunction in the cystic fibrosis transmembrane conductance regulator (CFTR), affects multiple organs through mucus obstruction and differences in secretion. The CFTR modulator drug combination elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA, ETI) has markedly improved clinical symptoms, but its broader molecular and systemic effects remain to be fully elucidated. We employed mass spectrometry-based proteomics to compare the plasma and serum proteomes of person with CF (pwCF) treated with the earlier, less effective lumacaftor/ivacaftor (LUM/IVA) combination against those receiving the more potent ELX/TEZ/IVA therapy. Our analysis revealed both specific and common pharmacodynamic signatures associated with inflammation and metabolic processes under each treatment regimen. Notably, ELX/TEZ/IVA therapy exhibited more consistent alterations across pwCF that were directed towards profiles observed in healthy individuals. Furthermore, by comparing sputum and serum proteomes of ELX/TEZ/IVA treated pwCF we identified counter directional changes in the pulmonary surfactant-associated protein B, SFTPB, a potential biomarker of lung permeability, which also correlated with lung function improvements and could be validated in an independent cohort. This study provides a comprehensive resource that enhances our understanding of CFTR modulator-driven proteome alterations, offering insights to both systemic and local protein regulation in CF. Our findings indicate that ELX/TEZ/IVA promotes broader systemic health improvements, providing critical insights that could shape future therapeutic strategies in CF.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Plasma, Sputum, Blood Serum

DISEASE(S): Cystic Fibrosis

SUBMITTER: Marieluise Kirchner  

LAB HEAD: Philipp Mertins

PROVIDER: PXD071549 | Pride | 2026-04-14

REPOSITORIES: Pride