Three drugs work better than two
Cystic fibrosis is an inherited metabolic disorder that remains incurable. A genetic defect in the CFTR gene causes organs such as the lungs and pancreas to produce very thick mucus that blocks the airways and digestive tract. Thanks to modern therapies using CFTR modulators, patients’ life expectancy and quality of life have improved significantly in recent years. CFTR stands for “cystic fibrosis transmembrane conductance regulator,” a membrane protein that does not function properly in people with cystic fibrosis.
A team led by Dr. Philipp Mertins, Group Leader of the Proteomics Technology Platform jointly operated by the Max Delbrück Center and the Berlin Institute of Health at Charité (BIH), has now investigated for the first time how combination therapies using either two or three CFTR modulators affect the proteome – the complete set of proteins – in blood and lung cells from people with cystic fibrosis. As the researchers report in the journal “Cell Systems,” triple therapy performed better.
“With the combination of three drugs, we observed a much stronger shift toward a healthy molecular state,” says, Dr. Kerstin Fentker, a postdoctoral researcher in Mertins’ lab and first author of the study. Additional senior authors of the publication include Drs. Marcus Mall and Simon Gräber from Charité – Universitätsmedizin Berlin.
Biomarkers of successful treatment
The researchers analyzed proteins in lung secretions and blood samples collected from people with cystic fibrosis before and during treatment with either Lumacaftor and Ivacaftor, or the triple combination Elexacaftor, Tezacaftor, and Ivacaftor. “In general, signaling pathways associated with inflammatory and metabolic processes were significantly altered by the drugs,” says Mertins.
Comparing the proteomes of blood cells to that of lung cells also showed that therapy-related changes only partially overlapped between the two cell types. “These differences illustrate that local processes in the lungs and systemic reactions in the body are not necessarily identical,” explains Mall. “This is crucial if we want to understand which potential biomarkers are actually suitable for reliably tracking disease progression and treatment response.”
One protein in particular, called SFTPB (surfactant protein B), which is closely linked to lung function, changed significantly during treatment with the three-drug combination. “We were also able to replicate our results in samples from other groups of patients with cystic fibrosis,” adds Gräber. “Our findings clearly show that modern therapies influence the disease biology of cystic fibrosis not only locally in the lungs, but throughout the entire body.”
Text: Anke Brodmerkel
The study was funded by grants from the German Center for Child and Adolescent Health (DZKJ) and the Collaborative Research Center (SFB) 1449 of the German Research Foundation (DFG), which focuses on “Dynamic Hydrogels at Biointerfaces.”
Further information
- Proteomics Technology Platform
- Research Group Mall
- Press release from the German Center for Child and Adolescent Health (DZKJ)
- New triple therapy alleviates cystic fibrosis
Literature
Kerstin Fentker, Marieluise Kirchner, Matthias Ziehm, et al. (2026): “Systemic effects of cystic fibrosis transmembrane conductance regulator modulators on the plasma and serum proteome.” Cell Systems, DOI: 10.1016/j.cels.2026.101569
Contact
Dr. Philipp Mertins
Group Leader
Proteomics Technology Platform
Philipp.Mertins@mdc-berlin.de
- Max Delbrück Center
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The Max Delbrück Center for Molecular Medicine in the Helmholtz Association lays the foundation for the medicine of tomorrow through our discoveries of today. At locations in Berlin-Buch, Berlin-Mitte, Heidelberg, and Mannheim, interdisciplinary teams investigate the complexity of disease at the systems level – from molecules and cells to organs and entire organisms. Together with academic, clinical, and industry partners, and as part of global networks, we turn biological insights into innovations for early detection, personalized therapies, and disease prevention. Founded in 1992, the Max Delbrück Center is home to a vibrant, international research community of around 1,800 people from over 70 countries. We are 90 percent funded by the German federal government and 10 percent by the state of Berlin.
