Optimal correction of distinct CFTR folding mutants in rectal cystic fibrosis organoids

Johanna F. Dekkers, Ricardo A.Gogorza Gondra, Evelien Kruisselbrink, Annelotte M. Vonk, Hettie M. Janssens, Karin M. De Winter-De Groot, Cornelis K. Van Der Ent, Jeffrey M. Beekman

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

57 Citaten (Scopus)

Samenvatting

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.

Originele taal-2Engels
Pagina's (van-tot)451-458
Aantal pagina's8
TijdschriftEuropean Respiratory Journal
Volume48
Nummer van het tijdschrift2
DOI's
StatusGepubliceerd - 1 aug. 2016
Extern gepubliceerdJa

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