Tesevatinib ameliorates progression of polycystic kidney disease in rodent models of autosomal recessive polycystic kidney disease

Abstract

AIMTo investigate the therapeutic potential of tesevatinib (TSV), a unique multi-kinase inhibitor currently in Phase II clinical trials for autosomal dominant polycystic kidney disease (ADPKD), in well-defined rodent models of autosomal recessive polycystic kidney disease (ARPKD).METHODSWe administered TSV in daily doses of 7.5 and 15 mg/kg per day by I.P. to the well characterized bpk model of polycystic kidney disease starting at postnatal day (PN) 4 through PN21 to assess efficacy and toxicity in neonatal mice during postnatal development and still undergoing renal maturation. We administered TSV by oral gavage in the same doses to the orthologous PCK model (from PN30 to PN90) to assess efficacy and toxicity in animals where developmental processes are complete. The following parameters were assessed: Body weight, total kidney weight; kidney weight to body weight ratios; and morphometric determination of a cystic index and a measure of hepatic disease. Renal function was assessed by: Serum BUN; creatinine; and a 12 h urinary concentrating ability. Validation of reported targets including the level of angiogenesis and inhibition of angiogenesis (active VEGFR2/KDR) was assessed by Western analysis.RESULTSThis study demonstrates that: (1) in vivo pharmacological inhibition of multiple kinase cascades with TSV reduced phosphorylation of key mediators of cystogenesis: EGFR, ErbB2, c-Src and KDR; and (2) this reduction of kinase activity resulted in significant reduction of renal and biliary disease in both bpk and PCK models of ARPKD. The amelioration of disease by TSV was not associated with any apparent toxicity.CONCLUSIONThe data supports the hypothesis that this multi-kinase inhibitor TSV may provide an effective clinical therapy for human ARPKD.

Therapeutic Inhibition of VEGF Signaling and Associated Nephrotoxicities

“…In the bpk mouse model for autosomal recessive PKD, intraperitoneal injection of tesevatinib (a multikinase inhibitor targeting EGF receptor, HER2, and VEGFR) from postnatal days 4-21 attenuated cyst formation in the kidney and liver and reduced total kidney weight. 48 Treatment with the multitargeted TKI nintedanib attenuated renal fibrosis in wild-type mice subjected to unilateral ureteral obstruction and folic acid nephropathy. 49 In contrast to the renal benefit seen with multitargeted TKIs, inhibition of VEGFR2 alone with an antibody resulted in spontaneous renal cyst development when given perinatally in mice, 50 and giving 10-week-old mice axitinib (a TKI targeting primarily VEFGR1, VEGFR2, and VEGFR3) resulted in loss of glomerular capillary fenestrations as well as proteinuria.…”

Role of Bicaudal C1 in renal gluconeogenesis and its novel interaction with the CTLH complex

“…Large cystic kidneys showing hyperactivation of EGFR, Src and mTORC1 also develop in homozygous mutant bpk mutant mice owing to a frame-shifting mutation in one of two alternative transcripts of Bicc1 [ 9 – 12 ]. Consistent with a role in polycystin signalling, Bicc1 is required to increase PC2 mRNA and protein levels, and its own accumulation is inhibited in Pkd1 mutant kidneys [ 13 , 14 ].…”

Therapies for Childhood Polycystic Kidney Disease

“…Tesevatinib (TSV) previously known as KD-019, is a unique multi-kinase inhibitor that targets EGFR, c-Src and KDR. TSV was effective in slowing the proliferation of renal epithelia and cyst growth, slowing progression of fibrosis and slowing the loss of renal function in the BPK and orthologous PCK rat models of ARPKD [160].…”