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

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.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Nadia Ameen reports financial support was provided by Cystic Fibrosis Foundation. Nadia Ameen reports financial support was provided by National Institutes of Health. Nadia Ameen reports a relationship with Cystic Fibrosis Foundation that includes: funding grants. Nadia Ameen reports a relationship with National Institutes of Health that includes: funding grants. Nadia Ameen has patent N/A pending to N/A. The authors have expressed no conflicts of interest, and the manuscript has not been published previously nor is being considered concurrently by another publication. All authors have read and approved it. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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