CFTR, the cystic fibrosis (CF) gene-encoded epithelial anion channel, has a prominent role in driving chloride, bicarbonate and fluid secretion in the ductal cells of the exocrine pancreas. Whereas severe mutations in CFTR cause fibrosis of the pancreas in utero, CFTR mutants with residual function, or CFTR variants with a normal chloride but defective bicarbonate permeability (CFTR^BD), are associated with an enhanced risk of pancreatitis. Recent studies indicate that CFTR function is not only compromised in genetic but also in selected patients with an acquired form of pancreatitis induced by alcohol, bile salts or smoking. In this review, we summarize recent insights into the mechanism and regulation of CFTR-mediated and modulated bicarbonate secretion in the pancreatic duct, including the role of the osmotic stress/chloride sensor WNK1 and the scaffolding protein IRBIT, and current knowledge about the role of CFTR in genetic and acquired forms of pancreatitis. Furthermore, we discuss the perspectives for CFTR modulator therapy in the treatment of exocrine pancreatic insufficiency and pancreatitis and introduce pancreatic organoids as a promising model system to study CFTR function in the human pancreas, its role in the pathology of pancreatitis and its sensitivity to CFTR modulators on a personalized basis.

Background: Many affected by pancreatitis harbor rare variants of the cystic fibrosis (CF) gene, CFTR, which encodes an epithelial chloride/bicarbonate channel. We investigated CFTR function and the effect of CFTR modulator drugs in pancreatitis patients carrying CFTR variants. Methods: Next-generation sequencing was performed to identify CFTR variants. Sweat tests and nasal potential difference (NPD) assays were performed to assess CFTR function in vivo. Intestinal current measurement (ICM) was performed on rectal biopsies. Patient-derived intestinal epithelial monolayers were used to evaluate chloride and bicarbonate transport and the effects of a CFTR modulator combination: elexacaftor, tezacaftor and ivacaftor (ETI). Results: Of 32 pancreatitis patients carrying CFTR variants, three had CF-causing mutations on both alleles and yielded CF-typical sweat test, NPD and ICM results. Fourteen subjects showed a more modest elevation in sweat chloride levels, including three that were provisionally diagnosed with CF. ICM indicated impaired CFTR function in nine out of 17 non-CF subjects tested. This group of nine included five carrying a wild type CFTR allele. In epithelial monolayers, a reduction in CFTR-dependent chloride transport was found in six out of 14 subjects tested, whereas bicarbonate secretion was reduced in only one individual. In epithelial monolayers of four of these six subjects, ETI improved CFTR function. Conclusions: CFTR function is impaired in a subset of pancreatitis patients carrying CFTR variants. Mutations outside the CFTR locus may contribute to the anion transport defect. Bioassays on patient-derived intestinal tissue and organoids can be used to detect such defects and to assess the effect of CFTR modulators. (c) 2024 The Authors. Published by Elsevier B.V. on behalf of IAP and EPC. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Cystic fibrosis (CF) is caused by mutation of the CFTR gene, encoding an epithelial anion channel. Here we evaluated the effect of the modulator combination elexacaftor-tezacaftor-ivacaftor (ETI) on the function of four rare, poorly characterized CFTR variants: L383S, I507del, L1065P and R1066H. Intestinal organoids were obtained from subjects carrying the CFTR variants L383S, I507del, L1065P or R1066H in trans of a minimal function allele (class I mutation). Organoids and epithelial monolayers were used to assess the effect of ETI on CFTR protein abundance and CFTR-mediated chloride, bicarbonate, and fluid transport. In L383S-CFTR expressing cells, normal levels of fully glycosylated CFTR protein (C-band) were detected. In contrast, in I507del, L1065P or R1066H organoids, only partially glycosylated CFTR (B-band) was detected. Chloride/bicarbonate transport was severely impaired in epithelial monolayers prepared from these latter three variants, while anion transport of the L383S variant was affected to a moderate extent. ETI, but not ivacaftor alone, significantly enhanced CFTR-mediated chloride and bicarbonate transport in L1065P and R1066H monolayers, and stimulated fluid transport. A corresponding increase in the abundance of C-band protein was observed in both variants. ETI also modestly improved L383S-CFTR function, with a marginal effect on I507del-CFTR. The I507del, L1065P and R1066H variants display severely impaired function. ETI treatment markedly enhanced L1065P- and R1066HCFTR function, whereas its effect on L383S- CFTR was less pronounced. Consequently, ETI may ameliorate disease symptoms in individuals carrying the L1065P or R1066H variant. More tentative, it may also benefit those carrying the L383S variant.