Optimal correction of distinct CFTR folding mutants in rectal cystic fibrosis organoids.
Small-molecule therapies that restore defects in cystic fibrosis transmembrane conductance regulator (CFTR) gating (potentiators) or trafficking (correctors) are being developed for cystic fibrosis (CF) in a mutation-specific fashion. Options for pharmacological correction of CFTR-p.Phe508del (F508del) are being extensively studied but correction of other trafficking mutants that may also benefit from corrector treatment remains largely unknown.We studied correction of the folding mutants CFTR-p.Phe508del, -p.Ala455Glu (A455E) and -p.Asn1303Lys (N1303K) by VX-809 and 18 other correctors (C1-C18) using a functional CFTR assay in human intestinal CF organoids.Function of both CFTR-p.Phe508del and -p.Ala455Glu was enhanced by a variety of correctors but no residual or corrector-induced activity was associated with CFTR-p.Asn1303Lys. Importantly, VX-809-induced correction was most dominant for CFTR-p.Phe508del, while correction of CFTR-p.Ala455Glu was highest by a subgroup of compounds called bithiazoles (C4, C13, C14 and C17) and C5.These data support the development of mutation-specific correctors for optimal treatment of different CFTR trafficking mutants, and identify C5 and bithiazoles as the most promising compounds for correction of CFTR-p.Ala455Glu.
Dept of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Centre, Utrecht, The Netherlands Laboratory of Translational Immunology, Wilhelmina Children's Hospital, University Medical Centre, Utrecht, The Netherlands.
Johanna F
JF
Dekkers
Dept of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Centre, Utrecht, The Netherlands Laboratory of Translational Immunology, Wilhelmina Children's Hospital, University Medical Centre, Utrecht, The Netherlands.
Ricardo A
RA
Gogorza Gondra
Dept of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Centre, Utrecht, The Netherlands Laboratory of Translational Immunology, Wilhelmina Children's Hospital, University Medical Centre, Utrecht, The Netherlands.
Evelien
E
Kruisselbrink
Dept of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Centre, Utrecht, The Netherlands Laboratory of Translational Immunology, Wilhelmina Children's Hospital, University Medical Centre, Utrecht, The Netherlands.
Annelotte M
AM
Vonk
Dept of Pediatric Pulmonology, Sophia Children's Hospital/Erasmus MC-University Medical Center, Rotterdam, The Netherlands.
Hettie M
HM
Janssens
Dept of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Centre, Utrecht, The Netherlands.
Karin M
KM
de Winter-de Groot
Dept of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Centre, Utrecht, The Netherlands.
Cornelis K
CK
van der Ent
Dept of Pediatric Pulmonology, Wilhelmina Children's Hospital, University Medical Centre, Utrecht, The Netherlands Laboratory of Translational Immunology, Wilhelmina Children's Hospital, University Medical Centre, Utrecht, The Netherlands J.Beekman@umcutrecht.nl.
Jeffrey M
JM
Beekman
D000631:Aminopyridines / Q000494:pharmacology; D052117:Benzodioxoles / Q000494:pharmacology; D001706:Biopsy; D003550:Cystic Fibrosis / Q000188:drug therapy* / Q000235:genetics*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D005838:Genotype; D006720:Homozygote; D006801:Humans; D009154:Mutation; D009940:Organoids; D017510:Protein Folding; D021381:Protein Transport; D012007:Rectum / Q000473:pathology; D013844:Thiazoles / Q000737:chemistry; D016896:Treatment Outcome
D000631:Aminopyridines; D052117:Benzodioxoles; C505032:CFTR protein, human; D013844:Thiazoles; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C569105:lumacaftor