Ivacaftor (Kalydeco) treatment improves airway flexibility and capacity in patients with cystic fibrosis (CF), according to the results of a study, “Acute administration of ivacaftor to people with cystic fibrosis and a G551D-CFTR mutation reveals smooth muscle abnormalities,” published in the Journal of Clinical Investigation Insight (JCI Insight).
CF is caused by the loss or dysfunction of the CF transmembrane conductance regulator (CFTR) channel activity, as a result of mutations in the Cftr gene. Absence of CFTR functional protein leads to the thick buildup of mucus, primarily in the lungs, which can clog the airways. The underlying mechanisms responsible for airway obstruction, however, remain incompletely understood. Abnormalities in airway smooth muscle (ASM), including increased smooth muscle mass, bronchodilator responsiveness, and airway hyper-reactivity, are often present in CF patients.
Researchers hypothesized that CFTR loss is the primary cause leading to defects in ASM function, and restoring CFTR activity would decrease smooth muscle tone in CF patients. To investigate this hypothesis, they potentiated CFTR function by administrating ivacaftor to 12 adults with CF and the G551D-CFTR mutation. Ivacaftor is a drug used to treat CF in people with certain mutations, and has been shown to increase CFTR activity in those with CFTR gating mutations.
The team studied patients before treatment, and had them perform tests including spirometry, whole-lung inspiratory, and expiratory chest CT scanning, and non-invasive measures of vascular tone. After starting ivacaftor therapy (48 hours later), patients returned to the clinic and repeated the exams. CFTR function was determined by measuring sweat chloride concentrations.
Results indicated that ivacaftor rapidly restored CFTR function, as shown by decreased sweat chloride concentration. Increased CFTR function was accompanied by significant improvements in airflow obstruction and air trapping. The team also assessed smooth muscle function in a tissue outside the lung, and observed that the vascular pulse wave velocity, and augmentation index, decreased following CFTR function potentiation.
In conclusion, ivacaftor treatment was seen to induce rapid improvements in the capacity and flexibility of small airways and vascular tone. This suggests that loss of CFTR may be the primary mechanism causing increased smooth muscle tone in CF patients.