The sodium/glucose cotransporters as potential therapeutic targets for CF lung diseases revealed by human lung organoid swelling assay

Hiroyuki Hirai*, Xiubin Liang, Yifei Sun, Yihan Zhang, Jifeng Zhang, Y. Eugene Chen, Hongmei Mou, Youyang Zhao, Jie Xu

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Cystic fibrosis (CF) is a lethal autosomal-recessive inherited disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. In the present work, we derived human proximal lung organoids (HLOs) from patient-derived pluripotent stem cells (PSCs) carrying disease-causing CFTR mutations. We evaluated the forskolin (Fsk)-stimulated swellings of these HLOs in the presence of CFTR modulators (VX-770 and/or VX-809) and demonstrated that HLOs respond to CFTR modulators in a mutation-dependent manner. Using this assay, we examined the effects of the sodium-dependent glucose cotransporter 1/2 (SGLT1/2) inhibitor drugs phlorizin and sotagliflozin on the basis of our findings that SGLT1 expression is upregulated in CF HLOs and airway epithelial cells compared with their wild-type counterparts. Unexpectedly, both drugs promoted dF/dF HLO swelling. These results reveal SGLTs, especially SGLT1, as potential therapeutic targets for treating CF lung diseases and demonstrate the use of PSC-derived HLOs as a preclinical tool in CF drug development.

Original languageEnglish (US)
Pages (from-to)11-19
Number of pages9
JournalMolecular Therapy - Methods and Clinical Development
Volume24
DOIs
StatePublished - Mar 10 2022

Keywords

  • CFTR
  • SGLT
  • cystic fibrosis
  • drug discovery
  • human induced pluripotent stem cells (hiPSCs)
  • inhibitor
  • lung organoids
  • sodium/glucose cotransporters
  • sotagliflozin

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

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