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

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 clin...

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Autores principales: Favia, Maria, Gallo, Crescenzio, Guerra, Lorenzo, De Venuto, Domenica, Diana, Anna, Polizzi, Angela Maria, Montemurro, Pasqualina, Mariggiò, Maria Addolorata, Leonetti, Giuseppina, Manca, Antonio, Casavola, Valeria, Conese, Massimo
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7177453/
https://www.ncbi.nlm.nih.gov/pubmed/32244302
http://dx.doi.org/10.3390/ijms21072398
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author Favia, Maria
Gallo, Crescenzio
Guerra, Lorenzo
De Venuto, Domenica
Diana, Anna
Polizzi, Angela Maria
Montemurro, Pasqualina
Mariggiò, Maria Addolorata
Leonetti, Giuseppina
Manca, Antonio
Casavola, Valeria
Conese, Massimo
author_facet Favia, Maria
Gallo, Crescenzio
Guerra, Lorenzo
De Venuto, Domenica
Diana, Anna
Polizzi, Angela Maria
Montemurro, Pasqualina
Mariggiò, Maria Addolorata
Leonetti, Giuseppina
Manca, Antonio
Casavola, Valeria
Conese, Massimo
author_sort Favia, Maria
collection PubMed
description 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 (FEV(1)%) 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, FEV(1)%, 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.
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spelling pubmed-71774532020-04-28 Treatment of Cystic Fibrosis Patients Homozygous for F508del with Lumacaftor-Ivacaftor (Orkambi(®)) Restores Defective CFTR Channel Function in Circulating Mononuclear Cells Favia, Maria Gallo, Crescenzio Guerra, Lorenzo De Venuto, Domenica Diana, Anna Polizzi, Angela Maria Montemurro, Pasqualina Mariggiò, Maria Addolorata Leonetti, Giuseppina Manca, Antonio Casavola, Valeria Conese, Massimo Int J Mol Sci Article 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 (FEV(1)%) 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, FEV(1)%, 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. MDPI 2020-03-31 /pmc/articles/PMC7177453/ /pubmed/32244302 http://dx.doi.org/10.3390/ijms21072398 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Favia, Maria
Gallo, Crescenzio
Guerra, Lorenzo
De Venuto, Domenica
Diana, Anna
Polizzi, Angela Maria
Montemurro, Pasqualina
Mariggiò, Maria Addolorata
Leonetti, Giuseppina
Manca, Antonio
Casavola, Valeria
Conese, Massimo
Treatment of Cystic Fibrosis Patients Homozygous for F508del with Lumacaftor-Ivacaftor (Orkambi(®)) Restores Defective CFTR Channel Function in Circulating Mononuclear Cells
title Treatment of Cystic Fibrosis Patients Homozygous for F508del with Lumacaftor-Ivacaftor (Orkambi(®)) Restores Defective CFTR Channel Function in Circulating Mononuclear Cells
title_full Treatment of Cystic Fibrosis Patients Homozygous for F508del with Lumacaftor-Ivacaftor (Orkambi(®)) Restores Defective CFTR Channel Function in Circulating Mononuclear Cells
title_fullStr Treatment of Cystic Fibrosis Patients Homozygous for F508del with Lumacaftor-Ivacaftor (Orkambi(®)) Restores Defective CFTR Channel Function in Circulating Mononuclear Cells
title_full_unstemmed Treatment of Cystic Fibrosis Patients Homozygous for F508del with Lumacaftor-Ivacaftor (Orkambi(®)) Restores Defective CFTR Channel Function in Circulating Mononuclear Cells
title_short Treatment of Cystic Fibrosis Patients Homozygous for F508del with Lumacaftor-Ivacaftor (Orkambi(®)) Restores Defective CFTR Channel Function in Circulating Mononuclear Cells
title_sort treatment of cystic fibrosis patients homozygous for f508del with lumacaftor-ivacaftor (orkambi(®)) restores defective cftr channel function in circulating mononuclear cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7177453/
https://www.ncbi.nlm.nih.gov/pubmed/32244302
http://dx.doi.org/10.3390/ijms21072398
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