Tolvaptan plus Pasireotide Shows Enhanced Efficacy in a PKD1 Model

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is a leading cause of ESRD. A central defect associated with ADPKD pathology is elevated levels of 39, 59-cyclic AMP (cAMP). Compounds such as tolvaptan and pasireotide, which indirectly reduce adenylyl cyclase 6 (AC6) activity, have hence proven effective in slowing cyst progression. Here, we tested the efficacy of these compounds individually and in combination in a hypomorphic PKD1 model, Pkd1 R3277C/R3277C (Pkd1 RC/RC ), in a 5-month preclinical trial. Initially, the Pkd1 RC/RC model was inbred into the C57BL/ 6 background, minimizing disease variability, and the pathogenic effect of elevating cAMP was confirmed by treatment with the AC6 stimulant desmopressin. Treatment with tolvaptan or pasireotide alone markedly reduced cyst progression and in combination showed a clear additive effect. Furthermore, combination treatment significantly reduced cystic and fibrotic volume and decreased cAMP to wild-type levels. We also showed that Pkd1 RC/RC mice experience hepatic hypertrophy that can be corrected by pasireotide. The observed additive effect reinforces the central role of AC6 and cAMP in ADPKD pathogenesis and highlights the likely benefit of combination therapy for patients with ADPKD.

Polycystin-1 maturation requires polycystin-2 in a dose-dependent manner

“…Crude membrane protein (75 μg) was isolated as described and the resulting membrane mice. This may be because in this combination no WT Pkd1 is present, although the level of PC1-NTR (5% reduced) may be most significant (46,57). A combined effect of both loci is consistent with the observations of PKD1 somatic mutations in PKD2 patient cysts (65), and vice versa (66), likely acting by lowering PC1-NTR below a cystogenic threshold and so favoring cyst development.…”

The Future of Polycystic Kidney Disease Research—As Seen By the 12 Kaplan Awardees

“…4 A mouse model mimicking the best characterized PKD1 hypomorphic allele, p.R3277C, recapitulates the human phenotypes with slowly progressive disease in homozygotes, generating a good model for preclinical testing, and rapidly progressive disease in compound heterozygotes with a null allele. 7,8 Detailed analysis of the model indicates that the level of the mature glycoform of the PKD1 protein (polycystin 1; PC1) is associated with disease severity, strongly supporting a dosage model of pathogenesis. Consistent with related mechanisms in cystic diseases, a combination of a PKD1 allele and mutations in a second cystogene can also result in severe PKD.…”

“…One approach that should be considered is the use of combination therapies, which can potentially increase efficacy and reduce toxicity. 8,86 …”

Effect of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease by CKD Stage: Results from the TEMPO 3:4 Trial

“…The suppression of vasopressin release by means of high water intake, genetic elimination of vasopressin, and vasopressin V2-receptor blockade all reduced cyst burden and protected kidney function in rodent models of the disease (4)(5)(6)(7)(8)(9)(10)(11)(12).…”