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

• Published in: Scientific reports Vol. 12; no. 1; p. 6132
• Main Authors: da Cunha, Mélanie Faria, Pranke, Iwona, Sassi, Ali, Schreiweis, Christiane, Moriceau, Stéphanie, Vidovic, Dragana, Hatton, Aurélie, Carlon, Mariane Sylvia, Creste, Geordie, Berhal, Farouk, Prestat, Guillaume, Freund, Romain, Odolczyk, Norbert, Jais, Jean Philippe, Gravier-Pelletier, Christine, Zielenkiewicz, Piotr, Jullien, Vincent, Hinzpeter, Alexandre, Oury, Franck, Edelman, Aleksander, Sermet-Gaudelus, Isabelle
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12-04-2022; Nature Publishing Group; Nature Portfolio
• Subjects: 631/80; 692/699; Animal models; Animals; Chloride conductance; Chloride transport; Chlorides; Cystic fibrosis; Cystic Fibrosis - genetics; Cystic Fibrosis Transmembrane Conductance Regulator - metabolism; Epithelial cells; Epithelium; Gene deletion; Human health and pathology; Humanities and Social Sciences; Ion Transport; Life Sciences; Mice; multidisciplinary; Mutation; Pharmaceutical sciences; Pharmacology; Phosphinic acid; Phosphinic Acids; Pulmonology and respiratory tract; Respiratory failure; Science; Science (multidisciplinary); Toxicity; Mutations; Cystic fibrosis
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/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
Cftr
tm1Eur
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
Cftr
tm1Eur
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.