Dekkers % 0期刊文章%,Johanna Gogor f %za Gondra, Ricardo A. %A Kruisselbrink, Evelien %A Vonk, Annelotte M. %A Janssens, Hettie M. %A de Winter-de Groot, Karin M. %A van der Ent, Cornelis K. %A Beekman, Jeffrey M. %T Optimal correction of distinct CFTR folding mutants in rectal cystic fibrosis organoids %D 2016 %R 10.1183/13993003.01192-2015 %J European Respiratory Journal %P 451-458 %V 48 %N 2 %X 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.CFTR corrector efficacy selectively depends on the type of folding and trafficking mutation http://ow.ly/ZrrzB %U //www.qdcxjkg.com/content/erj/48/2/451.full.pdf