Systemic bis-phosphinic acid derivative restores chloride transport in Cystic Fibrosis mice - Archive ouverte HAL Access content directly
Journal Articles Scientific Reports Year : 2022

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

(1, 2) , (2, 1) , (2, 1) , (1) , (1) , (3) , (1, 2) , (3) , (4, 2) , (4, 2) , (4, 2) , (2, 5) , (6) , (7) , (4, 2) , (6) , (8) , (1, 2) , (1, 2) , (1, 2) , (1, 2, 7, 9)
1
2
3
4
5
6
7
8
9

Abstract

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 aminoacid 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.
Fichier principal
Vignette du fichier
Systemic bis.pdf (1.55 Mo) Télécharger le fichier
Origin : Publisher files allowed on an open archive

Dates and versions

hal-03662932 , version 1 (09-05-2022)

Licence

Attribution - CC BY 4.0

Identifiers

Cite

Mélanie Faria da Cunha, Iwona Pranke, Ali Sassi, Christiane Schreiweis, Stéphanie Moriceau, et al.. Systemic bis-phosphinic acid derivative restores chloride transport in Cystic Fibrosis mice. Scientific Reports, 2022, 12 (1), pp.6132. ⟨10.1038/s41598-022-09678-9⟩. ⟨hal-03662932⟩
28 View
12 Download

Altmetric

Share

Gmail Facebook Twitter LinkedIn More