Systemic effects of cystic fibrosis transmembrane conductance regulator (CFTR) modulators on the blood proteome

Fentker, K.; Kirchner, M.; Ziehm, M.; Niquet, S.; Popp, O.; Duerr, J.; Schaupp, L.; Roehmel, J.; Thee, S.; Haemmerling, S.; Sommerburg, O.; Stahl, M.; Graeber, S. Y.; Mall, M. A.; Mertins, P.

doi:10.1101/2024.10.18.619058

bioRxiv · 10.1101/2024.10.18.619058

Systemic effects of cystic fibrosis transmembrane conductance regulator (CFTR) modulators on the blood proteome

Fentker, K.·Kirchner, M.·Ziehm, M.·Niquet, S.·Popp, O.·Duerr, J.·Schaupp, L.·Roehmel, J.·Thee, S.·Haemmerling, S.·Sommerburg, O.·Stahl, M.·Graeber, S. Y.·Mall, M. A.·Mertins, P.

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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 blood proteomes of CF patients 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 patients that were directed towards profiles observed in healthy individuals. Furthermore, by comparing sputum and blood proteomes of ELX/TEZ/IVA treated patients we identified counter-directional changes in the pulmonary surfactant-associated protein B, SFTPB, a potential biomarker of lung tissue repair, which also correlated with lung function improvements. 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.

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Fentker, K., Kirchner, M., Ziehm, M., Niquet, S., Popp, O., Duerr, J., Schaupp, L., Roehmel, J., Thee, S., Haemmerling, S., Sommerburg, O., Stahl, M., Graeber, S. Y., Mall, M. A., Mertins, P.. 2024-10-18. Systemic effects of cystic fibrosis transmembrane conductance regulator (CFTR) modulators on the blood proteome. https://doi.org/10.1101/2024.10.18.619058

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