title: Characterizing responses to CFTR-modulating drugs using rectal organoids derived from subjects with cystic fibrosis.
abstract: Identifying subjects with cystic fibrosis (CF) who may benefit from cystic fibrosis transmembrane conductance regulator (CFTR)-modulating drugs is time-consuming, costly, and especially challenging for individuals with rare uncharacterized CFTR mutations. We studied CFTR function and responses to two drugs-the prototypical CFTR potentiator VX-770 (ivacaftor/KALYDECO) and the CFTR corrector VX-809 (lumacaftor)-in organoid cultures derived from the rectal epithelia of subjects with CF, who expressed a broad range of CFTR mutations. We observed that CFTR residual function and responses to drug therapy depended on both the CFTR mutation and the genetic background of the subjects. In vitro drug responses in rectal organoids positively correlated with published outcome data from clinical trials with VX-809 and VX-770, allowing us to predict from preclinical data the potential for CF patients carrying rare CFTR mutations to respond to drug therapy. We demonstrated proof of principle by selecting two subjects expressing an uncharacterized rare CFTR genotype (G1249R/F508del) who showed clinical responses to treatment with ivacaftor and one subject (F508del/R347P) who showed a limited response to drug therapy both in vitro and in vivo. These data suggest that in vitro measurements of CFTR function in patient-derived rectal organoids may be useful for identifying subjects who would benefit from CFTR-correcting treatment, independent of their CFTR mutation.
authors.affiliation: Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Center Utrecht, 3584 EA Utrecht, Netherlands. Laboratory of Translational Immunology, Wilhelmina Children's Hospital, University Medical Center Utrecht, 3584 EA Utrecht, Netherlands.
authors.forename: Johanna F
authors.initials: JF
authors.lastname: Dekkers
authors.affiliation: Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Center Utrecht, 3584 EA Utrecht, Netherlands.
authors.forename: Gitte
authors.initials: G
authors.lastname: Berkers
authors.affiliation: Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Center Utrecht, 3584 EA Utrecht, Netherlands. Laboratory of Translational Immunology, Wilhelmina Children's Hospital, University Medical Center Utrecht, 3584 EA Utrecht, Netherlands.
authors.forename: Evelien
authors.initials: E
authors.lastname: Kruisselbrink
authors.affiliation: Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Center Utrecht, 3584 EA Utrecht, Netherlands. Laboratory of Translational Immunology, Wilhelmina Children's Hospital, University Medical Center Utrecht, 3584 EA Utrecht, Netherlands.
authors.forename: Annelotte
authors.initials: A
authors.lastname: Vonk
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus University Medical Center, 3015 CE Rotterdam, Netherlands.
authors.forename: Hugo R
authors.initials: HR
authors.lastname: de Jonge
authors.affiliation: Department of Pediatric Pulmonology, Erasmus University Medical Center/Sophia Children's Hospital, 3015 CN Rotterdam, Netherlands.
authors.forename: Hettie M
authors.initials: HM
authors.lastname: Janssens
authors.affiliation: Department of Pulmonology, University Medical Center Utrecht, 3584 CX Utrecht, Netherlands.
authors.forename: Inez
authors.initials: I
authors.lastname: Bronsveld
authors.affiliation: Department of Pulmonology, University Medical Center Utrecht, 3584 CX Utrecht, Netherlands.
authors.forename: Eduard A
authors.initials: EA
authors.lastname: van de Graaf
authors.affiliation: Department of Pediatric Gastroenterology, Wilhelmina Children's Hospital, University Medical Center Utrecht, 3584 EA Utrecht, Netherlands.
authors.forename: Edward E S
authors.initials: EE
authors.lastname: Nieuwenhuis
authors.affiliation: Department of Pediatric Gastroenterology, Wilhelmina Children's Hospital, University Medical Center Utrecht, 3584 EA Utrecht, Netherlands.
authors.forename: Roderick H J
authors.initials: RH
authors.lastname: Houwen
authors.affiliation: Department of Gastroenterology and Hepatology, University Medical Center Utrecht, 3584 CX Utrecht, Netherlands.
authors.forename: Frank P
authors.initials: FP
authors.lastname: Vleggaar
authors.affiliation: Department of Pediatric Gastroenterology, Erasmus University Medical Center/Sophia Children's Hospital, 3015 CN Rotterdam, Netherlands.
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Escher
authors.affiliation: Department of Clinical Chemistry, Erasmus University Medical Center/Sophia Children's Hospital, 3015 CN Rotterdam, Netherlands.
authors.forename: Yolanda B
authors.initials: YB
authors.lastname: de Rijke
authors.affiliation: Department of Respiratory Medicine, Academic Medical Center, 1105 AZ Amsterdam, Netherlands.
authors.forename: Christof J
authors.initials: CJ
authors.lastname: Majoor
authors.affiliation: Department of Pulmonology and Cystic Fibrosis, Haga Teaching Hospital, 2545 CH The Hague, Netherlands.
authors.forename: Harry G M
authors.initials: HG
authors.lastname: Heijerman
authors.affiliation: Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Center Utrecht, 3584 EA Utrecht, Netherlands.
authors.forename: Karin M
authors.initials: KM
authors.lastname: de Winter-de Groot
authors.affiliation: Hubrecht Institute for Developmental Biology and Stem Cell Research and University Medical Center Utrecht, 3584 CT Utrecht, Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Clevers
authors.affiliation: Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Center Utrecht, 3584 EA Utrecht, Netherlands.
authors.forename: Cornelis K
authors.initials: CK
authors.lastname: van der Ent
authors.affiliation: Department of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Center Utrecht, 3584 EA Utrecht, Netherlands. Laboratory of Translational Immunology, Wilhelmina Children's Hospital, University Medical Center Utrecht, 3584 EA Utrecht, Netherlands. Regenerative Medicine Center Utrecht, University Medical Center Utrecht, 3584 CX Utrecht, Netherlands. j.beekman@umcutrecht.nl.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Beekman
mesh_terms: D000627:Aminophenols / Q000494:pharmacology; D000631:Aminopyridines / Q000494:pharmacology; D052117:Benzodioxoles / Q000494:pharmacology; D001681:Biological Assay / Q000379:methods; D002712:Chlorides / Q000378:metabolism; D003550:Cystic Fibrosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D005838:Genotype; D006801:Humans; D066298:In Vitro Techniques; D009154:Mutation / Q000235:genetics; D009940:Organoids / Q000187:drug effects / Q000378:metabolism*; D015363:Quinolones / Q000494:pharmacology
chemical_list: D000627:Aminophenols; D000631:Aminopyridines; D052117:Benzodioxoles; C505032:CFTR protein, human; D002712:Chlorides; D015363:Quinolones; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C545203:ivacaftor; C569105:lumacaftor