Gene expression profile of intestinal organoids from people with cystic fibrosis upon exposure to elexacaftor/tezacaftor/ivacaftor
Language English Country Netherlands Media print-electronic
Document type Journal Article
PubMed
39278758
DOI
10.1016/j.jcf.2024.09.005
PII: S1569-1993(24)01713-2
Knihovny.cz E-resources
- Keywords
- Cystic fibrosis, Differential expression, Elexacaftor, Intestinal organoid, Ivacaftor, Tezacaftor,
- MeSH
- Chloride Channel Agonists pharmacology MeSH
- Aminophenols * pharmacology MeSH
- Benzodioxoles * pharmacology MeSH
- Quinolines MeSH
- Quinolones * pharmacology MeSH
- Cystic Fibrosis * genetics drug therapy MeSH
- Drug Combinations MeSH
- Indoles * pharmacology MeSH
- Humans MeSH
- Organoids * drug effects metabolism MeSH
- Cystic Fibrosis Transmembrane Conductance Regulator genetics MeSH
- Pyrazoles MeSH
- Pyridines * pharmacology MeSH
- Pyrrolidines MeSH
- Pyrroles * pharmacology MeSH
- Gene Expression Profiling MeSH
- Thiophenes pharmacology MeSH
- Transcriptome MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Chloride Channel Agonists MeSH
- Aminophenols * MeSH
- Benzodioxoles * MeSH
- Quinolines MeSH
- Quinolones * MeSH
- elexacaftor, ivacaftor, tezacaftor drug combination MeSH Browser
- elexacaftor MeSH Browser
- Drug Combinations MeSH
- Indoles * MeSH
- ivacaftor MeSH Browser
- Cystic Fibrosis Transmembrane Conductance Regulator MeSH
- Pyrazoles MeSH
- Pyridines * MeSH
- Pyrrolidines MeSH
- Pyrroles * MeSH
- tezacaftor MeSH Browser
- Thiophenes MeSH
The forskolin-induced swelling assay (FIS) in patient-derived intestinal organoids (PDIOs), used to determine in vitro responsiveness to elexacaftor/tezacaftor/ivacaftor (ETI), showed variability in swelling among PDIOs obtained from people with CF (pwCF) carrying the same F508del/F508del CFTR genotype. We aimed to characterise the effect of ETI on the transcriptional activity of PDIOs-derived cells to understand the intracellular processes triggered by ETI and the differences in treatment response. Six high- and six low-responding PDIOs to ETI, derived from F508del/F508del pwCF, were incubated with or without ETI for 2 to 6 h. Gene expression was assessed using 3'-mRNA sequencing and modelled using negative binomial models. Incubation with ETI resulted in a significant upregulation of several biological processes: mostly related to chemokines and signalling, chemotaxis, and tissue development processes. No changes were observed in abundance of the CFTR transcripts or in CFTR-related gene sets and pathways. The genes and pathways associated with ETI did not overlap with those whose expression changed with time only. PDIOs with a high FIS response did not significantly differ in any interpretable gene from the FIS-low organoids. The changes in the PDIOs gene expression upon the exposure to ETI cannot explain differences in the magnitude of PDIOs FIS-measured response to ETI. In conclusion, on incubation with ETI, genes of the CFTR-related pathways do not change their transcriptional activity; instead, overexpression was observed in genes of inflammatory-like cytokine response and receptor activation pathways.
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