CFTR‐dependent chloride efflux in cystic fibrosis mononuclear cells is increased by ivacaftor therapy

Abstract

In patients with non-G551D mutations, ivacaftor improved both chloride transport in sweat ducts and chloride efflux in MNC, that is, functions directly imputed to CFTR.

Treatment of Cystic Fibrosis Patients Homozygous for F508del with Lumacaftor-Ivacaftor (Orkambi®) Restores Defective CFTR Channel Function in Circulating Mononuclear Cells

“…The effects of CFTR modulators on pulmonary function, pulmonary exacerbations, sweat chloride concentration, and quality of life have been well documented, whereas less evidence is available on extrapulmonary manifestations, including inflammation and immunity [24]. A few studies have shown that ivacaftor increases innate immune cell activities, such as killing of P. aeruginosa by neutrophils and monocytes [25,26] and oxidative burst of neutrophils as mediated by enhanced expression of hydrogen voltage-gated channel-1 [22]. Interestingly, ivacaftor-lumacaftor (Orkambi ® ) treatment was not associated with improved phagocytosis and killing of P. aeruginosa by monocyte-derived macrophages [26].…”

“…As a novel biomarker for therapeutic efficacy in CF patients focused on immune cells, we investigated if and how CFTR-dependent chloride channel activity in MNCs was modified by ivacaftor in the past [22] and by Orkambi ® in the present study. Ivacaftor treatment of patients From the above correlations, we can highlight three well-defined groups ( Figure 4B): (i) CFTR activity, FEV 1 , sweat chloride, WBC, and BMI; (ii) platelets, neutrophils, lymphocytes, basophils, and eosinophils; and (iii) CRP and monocytes.…”

“…As a novel biomarker for therapeutic efficacy in CF patients focused on immune cells, we investigated if and how CFTR-dependent chloride channel activity in MNCs was modified by ivacaftor in the past [22] and by Orkambi ® in the present study. Ivacaftor treatment of patients harboring non-G551D gating mutations was associated with a significant increase in MNC CFTR channel activity and this response was paralleled by a decrease in sweat chloride concentration [22]. In the present study, CFTR channel activity increased significantly after 6 and 12 months of treatment with Orkambi ® of F508del/F508del patients while sweat chloride showed a significant decrease only at 6 months.…”

“…In the cohort of 14 patients, we analyzed whether treatment with Orkambi ® could influence CFTR-dependent chloride efflux in circulating MNCs. CFTR-dependent chloride efflux was analyzed by spectrofluorimetric analysis using the chloride-sensitive dye, MQAE, following a procedure that we developed [22]. The experimental conditions for the CFTR functional assay was established with MNCs obtained from healthy subjects.…”

“…In the search of novel and non-invasive biomarkers, which should be predictive of the therapeutic response in CF patients, we recently demonstrated [22] that human peripheral blood monocytes (MNCs) isolated from CF patients treated with ivacaftor could represent an important tool for the analysis of CFTR-dependent chloride efflux rescue and to evaluate the therapeutic response in CF patients. Furthermore, the correlation between MNC chloride efflux with FVC and FEV 1 indicates that this test could be a surrogate marker similar to the respiratory function parameters.…”