Damien Adam1, Claudia Bilodeau2, Laura Sognigbé3, Émilie Maillé4, Manon Ruffin5, Emmanuelle Brochiero6. 1. Centre de recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada; Département de médecine, Université de Montréal, Montréal, Québec, Canada. Electronic address: damien.adam@umontreal.ca. 2. Centre de recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada; Département de médecine, Université de Montréal, Montréal, Québec, Canada. Electronic address: claudia.bilodeau.1@gmail.com. 3. Centre de recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada; Département de médecine, Université de Montréal, Montréal, Québec, Canada. Electronic address: laura.sognigbe@umontreal.ca. 4. Centre de recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada. Electronic address: emilie.maille.chum@ssss.gouv.qc.ca. 5. Centre de recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada; Département de médecine, Université de Montréal, Montréal, Québec, Canada. Electronic address: manon.ruffin2@gmail.com. 6. Centre de recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Québec, Canada; Département de médecine, Université de Montréal, Montréal, Québec, Canada. Electronic address: emmanuelle.brochiero@umontreal.ca.
Abstract
BACKGROUND: Progressive airway damage due to bacterial infections, especially with Pseudomonas aeruginosa remains the first cause of morbidity and mortality in CF patients. Our previous work revealed a repair delay in CF airway epithelia compared to non-CF. This delay was partially prevented after CFTR correction (with VRT-325) in the absence of infection. Our goals were now to evaluate the effect of the Orkambi combination (CFTR VX-809 corrector + VX-770 potentiator) on the repair of CF primary airway epithelia, in infectious conditions. METHODS: Primary airway epithelial cell cultures from patients with class II mutations were mechanically injured and wound healing rates and transepithelial resistances were monitored after CFTR rescue, in the absence and presence of P. aeruginosa exoproducts. RESULTS: Our data revealed that combined treatment with VX-809 and VX-770 elicited a greater beneficial impact on airway epithelial repair than VX-809 alone, in the absence of infection. The treatment with Orkambi was effective not only in airway epithelial cell cultures from patients homozygous for the F508del mutation but also from heterozygous patients carrying F508del and another class II mutation (N1303 K, I507del). The stimulatory effect of the Orkambi treatment was prevented by CFTR inhibition with GlyH101. Finally, Orkambi combination elicited a slight but significant improvement in airway epithelial repair and transepithelial resistance, despite the presence of P. aeruginosa exoproducts. CONCLUSIONS: Our findings indicate that Orkambi may favor airway epithelial integrity in CF patients with class II mutations. Complementary approaches would however be needed to further improve CFTR rescue and airway epithelial repair.
BACKGROUND: Progressive airway damage due to bacterial infections, especially with Pseudomonas aeruginosa remains the first cause of morbidity and mortality in CFpatients. Our previous work revealed a repair delay in CF airway epithelia compared to non-CF. This delay was partially prevented after CFTR correction (with VRT-325) in the absence of infection. Our goals were now to evaluate the effect of the Orkambi combination (CFTR VX-809 corrector + VX-770 potentiator) on the repair of CF primary airway epithelia, in infectious conditions. METHODS: Primary airway epithelial cell cultures from patients with class II mutations were mechanically injured and wound healing rates and transepithelial resistances were monitored after CFTR rescue, in the absence and presence of P. aeruginosa exoproducts. RESULTS: Our data revealed that combined treatment with VX-809 and VX-770 elicited a greater beneficial impact on airway epithelial repair than VX-809 alone, in the absence of infection. The treatment with Orkambi was effective not only in airway epithelial cell cultures from patients homozygous for the F508del mutation but also from heterozygous patients carrying F508del and another class II mutation (N1303 K, I507del). The stimulatory effect of the Orkambi treatment was prevented by CFTR inhibition with GlyH101. Finally, Orkambi combination elicited a slight but significant improvement in airway epithelial repair and transepithelial resistance, despite the presence of P. aeruginosa exoproducts. CONCLUSIONS: Our findings indicate that Orkambi may favor airway epithelial integrity in CFpatients with class II mutations. Complementary approaches would however be needed to further improve CFTR rescue and airway epithelial repair.
Authors: Zsolt Bene; Zsolt Fejes; Tibor Gabor Szanto; Ferenc Fenyvesi; Judit Váradi; Luka A Clarke; Gyorgy Panyi; Milan Macek; Margarida D Amaral; István Balogh; Béla Nagy Journal: Front Pharmacol Date: 2021-05-14 Impact factor: 5.810
Authors: Karen Keown; Ryan Brown; Declan F Doherty; Claire Houston; Michael C McKelvey; Shannice Creane; Dermot Linden; Daniel F McAuley; Joseph C Kidney; Sinéad Weldon; Damian G Downey; Clifford C Taggart Journal: Int J Mol Sci Date: 2020-09-02 Impact factor: 5.923