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Systemic bis-phosphinic acid derivative restores chloride transport in Cystic Fibrosis mice

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dc.abstract.enMutations in the Cystic Fibrosis Transmembrane Conductance Regulator gene (CFTR) are responsible for Cystic Fibrosis (CF). The most common CF-causing mutation is the deletion of the 508th amino-acid of CFTR (F508del), leading to dysregulation of the epithelial fluid transport in the airway’s epithelium and the production of a thickened mucus favoring chronic bacterial colonization, sustained inflammation and ultimately respiratory failure. c407 is a bis-phosphinic acid derivative which corrects CFTR dysfunction in epithelial cells carrying the F508del mutation. This study aimed to investigate c407 in vivo activity in the F508del Cftrtm1Eur murine model of CF. Using nasal potential difference measurement, we showed that in vivo administration of c407 by topical, short-term intraperitoneal and long-term subcutaneous route significantly increased the CFTR dependent chloride (Cl−) conductance in F508del Cftrtm1Eur mice. This functional improvement was correlated with a relocalization of F508del-cftr to the apical membrane in nasal epithelial cells. Importantly, c407 long-term administration was well tolerated and in vitro ADME toxicologic studies did not evidence any obvious issue. Our data provide the first in vivo preclinical evidence of c407 efficacy and absence of toxicity after systemic administration for the treatment of Cystic Fibrosis.
dc.affiliationUniwersytet Warszawski
dc.contributor.authorSermet-Gaudelus, Isabelle
dc.contributor.authorEdelman, Aleksander
dc.contributor.authorOury, Franck
dc.contributor.authorHinzpeter, Alexandre
dc.contributor.authorJullien, Vincent
dc.contributor.authorZielenkiewicz, Piotr
dc.contributor.authorGravier-Pelletier, Christine
dc.contributor.authorJais, Jean Philippe
dc.contributor.authorOdolczyk, Norbert
dc.contributor.authorFreund, Romain
dc.contributor.authorPrestat, Guillaume
dc.contributor.authorBerhal, Farouk
dc.contributor.authorCreste, Geordie
dc.contributor.authorCarlon, Mariane Sylvia
dc.contributor.authorHatton, Aurélie
dc.contributor.authorVidovic, Dragana
dc.contributor.authorMoriceau, Stéphanie
dc.contributor.authorSchreiweis, Christiane
dc.contributor.authorSassi, Ali
dc.contributor.authorPranke, Iwona
dc.contributor.authorCunha, Mélanie Faria da
dc.date.accessioned2024-01-26T09:28:43Z
dc.date.available2024-01-26T09:28:43Z
dc.date.copyright2022-04-12
dc.date.issued2022
dc.description.accesstimeAT_PUBLICATION
dc.description.financeNie dotyczy
dc.description.number1
dc.description.versionFINAL_PUBLISHED
dc.description.volume12
dc.identifier.doi10.1038/S41598-022-09678-9
dc.identifier.issn2045-2322
dc.identifier.urihttps://repozytorium.uw.edu.pl//handle/item/121361
dc.identifier.weblinkhttps://www.nature.com/articles/s41598-022-09678-9.pdf
dc.languageeng
dc.pbn.affiliationbiological sciences
dc.relation.ispartofScientific Reports
dc.relation.pages6132 (1-9)
dc.rightsCC-BY
dc.sciencecloudnosend
dc.subject.plbrak
dc.titleSystemic bis-phosphinic acid derivative restores chloride transport in Cystic Fibrosis mice
dc.typeJournalArticle
dspace.entity.typePublication