TY - JOUR
T1 - Optimal correction of distinct CFTR folding mutants in rectal cystic fibrosis organoids
AU - Dekkers, Johanna F.
AU - Gondra, Ricardo A.Gogorza
AU - Kruisselbrink, Evelien
AU - Vonk, Annelotte M.
AU - Janssens, Hettie M.
AU - De Winter-De Groot, Karin M.
AU - Van Der Ent, Cornelis K.
AU - Beekman, Jeffrey M.
PY - 2016/8/1
Y1 - 2016/8/1
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84980016718&partnerID=8YFLogxK
U2 - 10.1183/13993003.01192-2015
DO - 10.1183/13993003.01192-2015
M3 - Article
C2 - 27103391
AN - SCOPUS:84980016718
SN - 0903-1936
VL - 48
SP - 451
EP - 458
JO - European Respiratory Journal
JF - European Respiratory Journal
IS - 2
ER -