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| Item Type: | Preprint |
|---|---|
| Title: | Systemic effects of cystic fibrosis transmembrane conductance regulator (CFTR) modulators on the blood proteome |
| Creators Name: | 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. and Mertins, P. |
| 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. |
| Source: | bioRxiv |
| Publisher: | Cold Spring Harbor Laboratory Press |
| Article Number: | 2024.10.18.619058 |
| Date: | 18 October 2024 |
| Official Publication: | https://doi.org/10.1101/2024.10.18.619058 |
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