Localization and function of humanized F508del-CFTR in mouse intestine following activation of serum glucocorticoid kinase 1 and Trikafta

Eur J Pharmacol. 2024 Sep 5:978:176771. doi: 10.1016/j.ejphar.2024.176771. Epub 2024 Jun 24.

Abstract

The CFTR modulator Trikafta has markedly improved lung disease for Cystic Fibrosis (CF) patients carrying the common delta F508 (F508del-CFTR) CFTR mutation. F508del-CFTR results in an apical trafficking defect and loss of function in CFTR-expressing epithelial cells. However, Trikafta has not resulted in improved gastrointestinal function in CF patients. A humanized mouse model of F508del-CFTR was recently generated to evaluate CFTR modulators and other compounds to treat human F508del-CFTR CF intestinal disease. Short-term (4 h) treatment of rats with Dexamethasone (Dex) potently activates serum glucocorticoid kinase 1 (SGK1) and increases CFTR apical traffic and ion transport in the native intestine. This study examined CFTR localization and ion transport in intestinal segments from humanized F508del-CFTR mice following treatment with Dex in the presence/absence of Trikafta. Dex treatment improved apical CFTR localization and function but was inconsistent along intestinal segments. Combined treatment with Dex and Trikafta was superior to Dex alone but inconsistently improved CFTR localization and function. These data suggest further optimization of humanized CF mouse models will be necessary to test the efficacy of compounds to treat human CF intestinal disease.

Keywords: CFTR; Cystic fibrosis; Intestine; SGK1; Trikafta.

MeSH terms

  • Animals
  • Benzodioxoles
  • Cystic Fibrosis / drug therapy
  • Cystic Fibrosis / genetics
  • Cystic Fibrosis / metabolism
  • Cystic Fibrosis Transmembrane Conductance Regulator* / deficiency
  • Cystic Fibrosis Transmembrane Conductance Regulator* / genetics
  • Cystic Fibrosis Transmembrane Conductance Regulator* / metabolism
  • Dexamethasone* / pharmacology
  • Enzyme Activation / drug effects
  • Humans
  • Indoles
  • Intestinal Mucosa / drug effects
  • Intestinal Mucosa / metabolism
  • Intestines / drug effects
  • Male
  • Mice
  • Mutation
  • Protein Serine-Threonine Kinases / deficiency
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Protein Transport / drug effects

Substances

  • Cystic Fibrosis Transmembrane Conductance Regulator
  • Dexamethasone
  • Protein Serine-Threonine Kinases
  • tezacaftor
  • Indoles
  • Benzodioxoles