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

Cystic fibrosis (CF) isa lethal autosomal-recessive inherited dis-ease 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 expres-sion 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.

Automated summary

This study derived human proximal lung organoids (HLOs) from patient-derived pluripotent stem cells (PSCs) carrying CFTR mutations, and found that HLOs responded to CFTR modulators in a mutation-dependent manner. The study also discovered that SGLT1 expression was upregulated in CF HLOs and airway epithelial cells, suggesting SGLT1 as a potential therapeutic target for CF lung diseases.