Kerstin Fentker (Berlin / DE), Marieluise Kirchner (Berlin / DE), Matthias Ziehm (Berlin / DE), Sylvia Niquet (Berlin / DE), Julia Duerr (Berlin / DE), Jobst Röhmel (Berlin / DE), Stephanie Thee (Berlin / DE), Susanne Hämmerling (Heidelberg / DE), Olaf Sommerburg (Heidelberg / DE), Mirjam Stahl (Berlin / DE), Simon Gräber (Berlin / DE), Marcus Mall (Berlin / DE), Philipp Mertins (Berlin / DE)
Cystic fibrosis (CF) is caused by a dysfunction in the cystic fibrosis transmembrane conductance regulator (CFTR) and affects multiple organs. It is characterized by mucus obstruction in the lungs and altered secretion in multiple organs including the pancreas, intestines, and liver. The novel CFTR modulator drug combination Elexacaftor/Tezacaftor/Ivacaftor (ELX/TEZ/IVA) has significantly improved symptoms for most patients with CF eligible for this therapy. Despite the notable benefits, it is crucial to note that modulator therapy does not constitute a cure for CF. This raises questions about the altered disease dynamics and ongoing clinical challenges in CF management.
This study compared longitudinal systemic treatment responses in the blood proteomes of cystic fibrosis patients using mass spectrometry. From a clinical perspective, the double combination of Lumacaftor/Ivacaftor (LUM/IVA) is less effective than the new and improved ELX/TEZ/IVA therapy, as shown by improved lung function and CFTR function, for example measured by sweat chloride concentration. We could identify specific and common pharmacodynamic signatures for both CFTR modulator treatments, affecting systemic inflammation and metabolic processes. While both treatments induce alterations in the blood proteome that correlate with ion channel and lung functions, the effects of ELX/TEZ/IVA were more robust, with a larger magnitude across patients and directed towards healthy signatures.
Additionally, we were able to compare the effects of ELX/TEZ/IVA treatment on the proteomes of lung-specific sputum samples with systemic effects in the blood. Among others, we observed counter-directional changes in the pulmonary surfactant-associated protein B, SFTPB. This development is a potential sign of lung repair that is absent in LUM/IVA treated patients. These findings indicate that ELX/TEZ/IVA not only inhibits further deterioration of lung function but also gradually improves the overall health status of patients.
This systems medicine study provides a resource of pharmacodynamic drug proteome alterations for CFTR modulator treatments and contributes to our understanding of systemic and local protein regulation in CF.