Three drugs work better than two

A combination of three drugs appears to more effectively treat people with cystic fibrosis than therapy with only two, concludes a study by Max Delbrück Center researchers published in ​“Cell Systems.” The study analyzed changes in the proteomes of blood and sputum samples from people with the disease.

 

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 sputum samples 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 and sputum samples also showed that therapy-related changes only partially overlapped between the two sample 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.”

 

Further information

 

Contact

Dr. Philipp Mertins
Group Leader
Proteomics Technology Platform
Philipp.​Mertins@​mdc-​berlin.​de

 

Back