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

da Cunha, Mélanie Faria and Pranke, Iwona and Sassi, Ali and Schreiweis, Christiane and Moriceau, Stéphanie and Vidovic, Dragana and Hatton, Aurélie and Carlon, Mariane Sylvia and Creste, Geordie and Berhal, Farouk and Prestat, Guillaume and Freund, Romain and Odolczyk, Norbert and Jais, Jean Philippe and Gravier-Pelletier, Christine and Zielenkiewicz, Piotr and Jullien, Vincent and Hinzpeter, Alexandre and Oury, Franck and Edelman, Aleksander and Sermet-Gaudelus, Isabelle (2022) Systemic bis-phosphinic acid derivative restores chloride transport in Cystic Fibrosis mice. Scientific reports, 12 (6132). ISSN ISSN 2045-2322 (online)

PDF - Accepted Version

Official URL: https://www.nature.com/articles/s41598-022-09678-9


Mutations 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.

Item Type:Article
Subjects:Q Science > Q Science (General)
R Medicine > RM Therapeutics. Pharmacology
Divisions:Department of Bioinformatics
ID Code:2232
Deposited By: Norbert Odolczyk
Deposited On:16 Jan 2023 14:09
Last Modified:16 Jan 2023 14:09

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