TY - JOUR
T1 - VX-809 mitigates disease in a mouse model of autosomal dominant polycystic kidney disease bearing the R3277C human mutation
AU - Yanda, Murali K.
AU - Cebotaru, Liudmila
N1 - Funding Information:
The work was funded by NIH Grant # DK125272 to LC The authors thank Deborah McClellan, PhD for editing the manuscript. We thank the Mayo Clinic Robert M. and Billie Kelley Pirnie Translational PDK Center for providing the mouse model. We thank William B. Guggino, PhD for scientific disucssions and help with the manuscript.
Funding Information:
The work was funded by NIH Grant # DK125272 to LC + +
Publisher Copyright:
© 2021 Federation of American Societies for Experimental Biology
PY - 2021/11
Y1 - 2021/11
N2 - Autosomal dominant polycystic kidney disease (ADPKD) is associated with the formation of renal cysts. We have devised a therapeutic approach, based on reversing the cyst phenotype from secretion to absorption by using VX-809, a modulator of the cystic fibrosis transmembrane regulator trafficking and processing. Our goal is to test VX-809 in RC/RC mice bearing the R3277C human mutation to demonstrate its therapeutic potential. We found that by 5 months of age, RC/RC mice had large cysts and impaired renal function, but when treated with VX-809 between the ages of 3 and 5 months, or 6 and 8 months, the cyst area was reduced in both groups, suggesting that VX-809 had shrunk previously existing cysts. After 2 months of treatment, the cyst size was lower than that of untreated animals of the same age. Our co-localization studies confirmed that cystic fibrosis transmembrane conductance regulator (CFTR) is found predominately at the apical membrane in the untreated animals of each age group, consistent with its role in Cl− secretion; after VX-809 treatment, the basolateral membrane co-localization of CFTR increased ~4-fold, accompanied by a decrease of ~2–3-fold in its apical co-localization, indicating that VX-809 alters the phenotype to favor fluid absorption. Sodium/hydrogen exchanger and epithelial sodium channel, found in normal kidneys at the apical membrane, were almost absent from the cysts. VX-809 restored both levels toward normal. HSP27 is highly expressed in RC/RC mice and lowered toward normal by VX-809. Our demonstration of cyst reduction, improved renal function, and generation of an absorptive phenotype all strongly support the therapeutic potential of VX-809 as a treatment for ADPKD. We show here in an animal model of slowly progressing cyst formation typical of human ADPKD that VX-809 reduces the growth of already established cysts. The magnitude of the effect in the RC/RC mouse model when compared to previous experiments using the same mouse model to evaluate tolvaptan indicates that CFTR modulators warrant further development as a treatment for ADPKD.
AB - Autosomal dominant polycystic kidney disease (ADPKD) is associated with the formation of renal cysts. We have devised a therapeutic approach, based on reversing the cyst phenotype from secretion to absorption by using VX-809, a modulator of the cystic fibrosis transmembrane regulator trafficking and processing. Our goal is to test VX-809 in RC/RC mice bearing the R3277C human mutation to demonstrate its therapeutic potential. We found that by 5 months of age, RC/RC mice had large cysts and impaired renal function, but when treated with VX-809 between the ages of 3 and 5 months, or 6 and 8 months, the cyst area was reduced in both groups, suggesting that VX-809 had shrunk previously existing cysts. After 2 months of treatment, the cyst size was lower than that of untreated animals of the same age. Our co-localization studies confirmed that cystic fibrosis transmembrane conductance regulator (CFTR) is found predominately at the apical membrane in the untreated animals of each age group, consistent with its role in Cl− secretion; after VX-809 treatment, the basolateral membrane co-localization of CFTR increased ~4-fold, accompanied by a decrease of ~2–3-fold in its apical co-localization, indicating that VX-809 alters the phenotype to favor fluid absorption. Sodium/hydrogen exchanger and epithelial sodium channel, found in normal kidneys at the apical membrane, were almost absent from the cysts. VX-809 restored both levels toward normal. HSP27 is highly expressed in RC/RC mice and lowered toward normal by VX-809. Our demonstration of cyst reduction, improved renal function, and generation of an absorptive phenotype all strongly support the therapeutic potential of VX-809 as a treatment for ADPKD. We show here in an animal model of slowly progressing cyst formation typical of human ADPKD that VX-809 reduces the growth of already established cysts. The magnitude of the effect in the RC/RC mouse model when compared to previous experiments using the same mouse model to evaluate tolvaptan indicates that CFTR modulators warrant further development as a treatment for ADPKD.
KW - CFTR
KW - VX-809
KW - absorption
KW - cysts
KW - polycystic kidney disease
KW - secretion
UR - http://www.scopus.com/inward/record.url?scp=85117940523&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85117940523&partnerID=8YFLogxK
U2 - 10.1096/fj.202101315R
DO - 10.1096/fj.202101315R
M3 - Article
C2 - 34662459
AN - SCOPUS:85117940523
SN - 0892-6638
VL - 35
JO - FASEB Journal
JF - FASEB Journal
IS - 11
M1 - e21987
ER -