TY - JOUR T1 - Optimal correction of distinct CFTR folding mutants in rectal cystic fibrosis organoids JF - European Respiratory Journal JO - Eur Respir J SP - 451 LP - 458 DO - 10.1183/13993003.01192-2015 VL - 48 IS - 2 AU - Johanna F. Dekkers AU - Ricardo A. Gogorza Gondra AU - Evelien Kruisselbrink AU - Annelotte M. Vonk AU - Hettie M. Janssens AU - Karin M. de Winter-de Groot AU - Cornelis K. van der Ent AU - Jeffrey M. Beekman Y1 - 2016/08/01 UR - http://erj.ersjournals.com/content/48/2/451.abstract N2 - 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 ER -