title: Limited premature termination codon suppression by read-through agents in cystic fibrosis intestinal organoids.
abstract: Premature termination codon read-through drugs offer opportunities for treatment of multiple rare genetic diseases including cystic fibrosis. We here analyzed the read-through efficacy of PTC124 and G418 using human cystic fibrosis intestinal organoids (E60X/4015delATTT, E60X/F508del, G542X/F508del, R1162X/F508del, W1282X/F508del and F508del/F508del). G418-mediated read-through induced only limited CFTR function, but functional restoration of CFTR by PTC124 could not be confirmed. These studies suggest that better read-through agents are needed for robust treatment of nonsense mutations in cystic fibrosis.
authors.affiliation: Laboratory of Translational Immunology, UMC Utrecht, The Netherlands.
authors.forename: D D
authors.initials: DD
authors.lastname: Zomer-van Ommen
authors.affiliation: Laboratory of Translational Immunology, UMC Utrecht, The Netherlands.
authors.forename: L A W
authors.initials: LA
authors.lastname: Vijftigschild
authors.affiliation: Laboratory of Translational Immunology, UMC Utrecht, The Netherlands.
authors.forename: E
authors.initials: E
authors.lastname: Kruisselbrink
authors.affiliation: Laboratory of Translational Immunology, UMC Utrecht, The Netherlands.
authors.forename: A M
authors.initials: AM
authors.lastname: Vonk
authors.affiliation: Laboratory of Translational Immunology, UMC Utrecht, The Netherlands.
authors.forename: J F
authors.initials: JF
authors.lastname: Dekkers
authors.affiliation: Dept of Pediatrics, Sophia Children's Hospital/Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
authors.forename: H M
authors.initials: HM
authors.lastname: Janssens
authors.affiliation: Dept of Pediatric Pulmonology, Wilhelmina Children's Hospital, UMC Utrecht, The Netherlands.
authors.forename: K M
authors.initials: KM
authors.lastname: de Winter-de Groot
authors.affiliation: Dept of Pediatric Pulmonology, Wilhelmina Children's Hospital, UMC Utrecht, The Netherlands.
authors.forename: C K
authors.initials: CK
authors.lastname: van der Ent
authors.affiliation: Laboratory of Translational Immunology, UMC Utrecht, The Netherlands; Dept of Pediatric Pulmonology, Wilhelmina Children's Hospital, UMC Utrecht, The Netherlands. Electronic address: J.Beekman@umcutrecht.nl.
authors.forename: J M
authors.initials: JM
authors.lastname: Beekman
mesh_terms: D002478:Cells, Cultured; D003049:Coccidiostats / Q000627:therapeutic use; D018389:Codon, Nonsense / Q000187:drug effects*; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D005839:Gentamicins / Q000627:therapeutic use*; D006801:Humans; D009940:Organoids / Q000166:cytology*; D010069:Oxadiazoles / Q000627:therapeutic use*; D012313:RNA / Q000235:genetics
chemical_list: D003049:Coccidiostats; D018389:Codon, Nonsense; D005839:Gentamicins; D010069:Oxadiazoles; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D012313:RNA; C010680:antibiotic G 418; C515878:ataluren
keywords: Cystic fibrosis; G418; Intestinal organoids; Nonsense suppression; PTC124; Read-through