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 language | English (US) |
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Pages (from-to) | 11-19 |
Number of pages | 9 |
Journal | Molecular Therapy - Methods and Clinical Development |
Volume | 24 |
DOIs | |
State | Published - 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