About this Research Topic
Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes for an ion channel mediating chloride and bicarbonate transport across epithelial cells. Following the approval of several CFTR therapies, a number of research groups have shown that the combination of corrector molecules (e.g., lumacaftor (VX-809) or tezacaftor (VX-661)) with a potentiator (e.g., ivacaftor (VX-770)) further enhanced the rescue of F508del-CFTR, the most common CF-causing mutation, when compared to single treatments with lumacaftor or tezacaftor. These findings led to the development of elexacaftor (VX-445), a nover corrector that together with tezacaftor and ivacaftor has been recently brought into the clinic and is known as highly effective CFTR modulators: Trikafta/KaftrioTM.
Lack of CFTR function causes the accumulation of thick mucus in the lungs, intestine, and pancreatic ducts. In CF lungs, increased mucus Viscoelasticity is associated with decreased mucociliary clearance and defects in host defense mechanisms. Highly effective CFTR modulators have been developed as therapies (i.e. Trikafta) for the major CF-causing mutation, F508del-CFTR. Phase 3 clinical trials with TrikaftaTM have shown remarkable improvement in lung function, reduction of pulmonary exacerbations, and improvement in the quality of life of CF patients carrying at least one copy of the F508del mutation. However, the impact of Trikafta on rare CFTR mutations and/or mucus properties is less known. Currently, academic and pharmaceutical laboratories are developing novel therapeutical approaches using patient-derived tissues and in vitro screening to establish personalized treatment testing novel CFTR modulators that could prove to be valuable to individual patients.
The aim of this Research Topic is to shed light on the molecular consequence of rare CFTR mutations and the ability of clinically-approved or novel CFTR modulators to restore it;
- Structural studies and molecular dynamic studies of modulator binding and their pro-folding action
- CFTR modulator effects on downstream players of CFTR dysfunction, such as inflammation, infection, and biochemical/biophysical mucus properties.
Lack of CFTR function causes the accumulation of thick mucus in the lungs, intestine, and pancreatic ducts. In CF lungs, increased mucus Viscoelasticity is associated with decreased mucociliary clearance and defects in host defense mechanisms. Highly effective CFTR modulators have been developed as therapies (i.e. Trikafta) for the major CF-causing mutation, F508del-CFTR. Phase 3 clinical trials with TrikaftaTM have shown remarkable improvement in lung function, reduction of pulmonary exacerbations, and improvement in the quality of life of CF patients carrying at least one copy of the F508del mutation. However, the impact of Trikafta on rare CFTR mutations and/or mucus properties is less known. Currently, academic and pharmaceutical laboratories are developing novel therapeutical approaches using patient-derived tissues and in vitro screening to establish personalized treatment testing novel CFTR modulators that could prove to be valuable to individual patients.
The aim of this Research Topic is to shed light on the molecular consequence of rare CFTR mutations and the ability of clinically-approved or novel CFTR modulators to restore it;
- Structural studies and molecular dynamic studies of modulator binding and their pro-folding action
- CFTR modulator effects on downstream players of CFTR dysfunction, such as inflammation, infection, and biochemical/biophysical mucus properties.
Keywords: Cystic Fibrosis, CFTR, correctors, potentiators, mucus
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