Basic Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Nephrol. Jul 6, 2017; 6(4): 188-200
Published online Jul 6, 2017. doi: 10.5527/wjn.v6.i4.188
Tesevatinib ameliorates progression of polycystic kidney disease in rodent models of autosomal recessive polycystic kidney disease
William E Sweeney, Philip Frost, Ellis D Avner
William E Sweeney, Ellis D Avner, Children’s Research Institute, Children’s Hospital Health System of Wisconsin and the Medical College of Wisconsin, Medical College of Wisconsin, Milwaukee, WI 53226, United States
Philip Frost, Calesca Pharmaceuticals, Inc., Dover, DE 19901, United States
Author contributions: Sweeney WE, Frost P and Avner ED all contributed substantially to the conception and design of this study, analysis and interpretation of data; all authors drafted the article and made critical revisions related to the intellectual content of the manuscript, and approved the final version of the article to be published.
Supported by The PKD research program is provided by the Children’s Research Institute, the Lillian Goldman Charitable Trust, Ellsworth Family and Children’s Foundation of Children’s Hospital and Health System of Wisconsin.
Institutional animal care and use committee statement: All animal experiments were conducted in accordance with policies of the NIH Guide for the Care and Use of Laboratory Animals and the Institutional Animal Care and Use Committee (IACUC) of the Medical College of Wisconsin. The IACUC at the Medical College of Wisconsin is properly appointed according to PHS policy IV.A.3.a and is qualified through the experience and expertise of its members to oversee the Institution’s animal care and use program. The Animal Welfare Assurance for the Medical College of Wisconsin is A3102-01. Specific protocols used in this study were approved by the Medical College of Wisconsin IACUC (approved protocols are AUA 4278 and AUA 4179).
Conflict-of-interest statement: The authors have no conflict of interest to declare. Conflict of Interest in Research statements are on file with the institution as per Medical College of Wisconsin policy #RS.GN.020.
Data sharing statement: Data sets and statistical methods are available upon request from the corresponding author.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Ellis D Avner, MD, Emeritus Professor of Pediatrics and Physiology, Founding Director, Children’s Research Institute, Children’s Hospital Health System of Wisconsin and the Medical College of Wisconsin, Medical College of Wisconsin, Suite C-510, Mailstop CCC C510, 999 North 92nd Street, Milwaukee, WI 53226, United States. bsweeney@mcw.edu
Telephone: +1-414-9555773 Fax: +1-414-3377105
Received: February 10, 2017
Peer-review started: February 15, 2017
First decision: March 8, 2017
Revised: May 2, 2017
Accepted: May 12, 2017
Article in press: May 13, 2017
Published online: July 6, 2017
Abstract
AIM

To 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).

METHODS

We 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.

RESULTS

This 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.

CONCLUSION

The data supports the hypothesis that this multi-kinase inhibitor TSV may provide an effective clinical therapy for human ARPKD.

Keywords: Autosomal recessive, Autosomal dominant, Polycystic kidney disease, Therapy, Kinase inhibition, Multi-kinase inhibitor, Phosphorylation, Renal cysts, Biliary, G-protein coupled receptor

Core tip: This study examined the effect of a multi-kinase inhibitor, tesevatinib (TSV) on cyst development and growth in rodent models of autosomal recessive polycystic kidney disease (ARPKD). Tesevatinib which targets epidermal growth factor receptors, Src and KDR is currently in clinical trials for autosomal dominant polycystic kidney disease (ADPKD) and given the molecular and cellular interactions of the ADPKD and ARPKD genes and proteins we sought to determine if TSV would ameliorate ARPKD TSV was tested in two well described models of ARPKD, the BPK a phenocopy, and an orthologous rat model of ARPKD, the PCK. Of particular interest was the effect of TSV’s inhibition of VEGFR2 or KDR during early post-natal development and renal maturation.