Abstract
The treatment of cystic fibrosis (CF) patients homozygous for the F508del mutation with Orkambi®, a combination of a corrector (lumacaftor) and a potentiator (ivacaftor) of the mutated CFTR protein, resulted in some amelioration of the respiratory function. However, a great variability in the clinical response was also observed. The aim of this study was to evaluate the response to Orkambi® in a small cohort of F508del/F508del patients (n = 14) in terms of clinical and laboratory parameters, including ex vivo CFTR activity in mononuclear cells (MNCs), during a 12-month treatment. Patients responded with an increase in percent predicted forced expiratory volume in 1 s (FEV1%) and body mass index (BMI) as well as with a decrease in white blood cell (WBC) total counts and serum C-reactive protein (CRP) levels, although not significantly. Sweat chloride and CFTR-dependent chloride efflux were found to decrease and increase, respectively, as compared with pre-therapy values. CFTR and BMI showed a statistically significant correlation during Orkambi® treatment. Clustering analysis showed that CFTR, BMI, sweat chloride, FEV1%, and WBC were strongly associated. These data support the notion that CFTR-dependent chloride efflux in MNCs should be investigated as a sensitive outcome measure of Orkambi® treatment in CF patients.
Highlights
Cystic fibrosis (CF) is an autosomal recessive disorder due to mutations occurring in the CFTR (CF Transmembrane Conductance Regulator) gene, encoding for a chloride-conducting channel located at the apical membrane of epithelial cells
After passing the endoplasmic reticulum quality control, CFTR is translocated to the Golgi complex where it is fully glycosylated and subsequently transported and inserted into the apical membrane of polarized cells, where it is subjected to endocytosis and recycled to the plasma membrane or targeted for lysosomal degradation [3,4,5]
A pre-planned pooled analysis, suggests that treatment with Orkambi® was associated with improvements in body mass index (BMI), the magnitude of improvement was of uncertain clinical significance [29]
Summary
Cystic fibrosis (CF) is an autosomal recessive disorder due to mutations occurring in the CFTR (CF Transmembrane Conductance Regulator) gene, encoding for a chloride-conducting channel located at the apical membrane of epithelial cells. CFTR is a glycosylated protein that functions as a chloride channel regulated by cAMP and protein kinase A (PKA)-mediated phosphorylation [2]. After passing the endoplasmic reticulum quality control, CFTR is translocated to the Golgi complex where it is fully glycosylated and subsequently transported and inserted into the apical membrane of polarized cells, where it is subjected to endocytosis and recycled to the plasma membrane or targeted for lysosomal degradation [3,4,5]. In the respiratory system of patients affected by CF, there is a defective Cl− secretion, a NaCl hyperabsorption, a depletion of airway surface liquid, and a secondary failure of mucociliary clearance [9] associated with an exaggerated immune response and impairment of lung function [10]
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