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

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 sodium/glucose cotransporter 1/2 (SGLT1/2) inhibitor drugs phlorizin and Sotagliflozin, based on our findings that SGLT1 expression is upregulated in CF HLOs and airway epithelial cells comparing to 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.