VX‐809 mitigates disease in a mouse model of autosomal dominant polycystic kidney disease bearing the R3277C human mutation

Abstract

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 colocalization 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 How to cite this article: Yanda MK, Cebotaru L. VX-809 mitigates disease in a mouse model of autosomal dominant polycystic kidney disease bearing the R3277C human mutation.

SARS-CoV-2-Mediated Lung Edema and Replication Are Diminished by Cystic Fibrosis Transmembrane Conductance Regulator Modulators

“…8G ) with more obvious effects when both modulators were used. These results suggest that CFTR modulators might also have an anti-inflammatory effect during SARS-CoV-2 infection ( 39 – 41 ).…”

Drugs in Clinical Development to Treat Autosomal Dominant Polycystic Kidney Disease

“…Together, these effects were hypothesized to promote net resorption of cyst fluid and thereby reduce cyst growth [ 93 , 94 ]. A follow-up study by the same authors produced similar results on cyst growth, while also preserving renal function in VX-809 treated PKD1 RC/RC mice [ 95 ].…”

Review of the Use of Animal Models of Human Polycystic Kidney Disease for the Evaluation of Experimental Therapeutic Modalities

“…Recently, these strains have been used in the experimental administration of drugs affecting the signaling pathways altered by Pkd1 mutations. The following drugs showed ameliorative effects on renal disease progression ( Table 1 ): AMPK activators, metformin [ 64 ], lixivaptan (a novel AVPR2 antagonist), with R-568 (a calcium receptor agonist for a combined inhibitory effect) [ 65 ], BLU2864, a PKA inhibitor [ 66 ], a CFTR-trafficking and processing modulator, VX-809, [ 67 ], nintedanib, a tyrosine kinase inhibitor [ 68 ], and a combination treatment with tolvaptan (an AVPV2 receptor antagonist), and pasireotide (a somatostatin analog) [ 69 ].…”