Prioritization of novel ADPKD drug candidates from disease-stage specific gene expression profiles.

Tareq B Malas,Peter A.C 'T Hoen,Kristina M Hettne,Wouter N Leonhard,Gerard J.P Van Westen,Dorien J.M Peters,Hester Bange,Leo S Price,Zoraide Granchi

doi:10.1016/j.ebiom.2019.11.046

Abstract

BackgroundAutosomal Dominant Polycystic Kidney Disease (ADPKD) is one of the most common causes of end-stage renal failure, caused by mutations in PKD1 or PKD2 genes. Tolvaptan, the only drug approved for ADPKD treatment, results in serious side-effects, warranting the need for novel drugs.MethodsIn this study, we applied RNA-sequencing of Pkd1cko mice at different disease stages, and with/without drug treatment to identify genes involved in ADPKD progression that were further used to identify novel drug candidates for ADPKD. We followed an integrative computational approach using a combination of gene expression profiling, bioinformatics and cheminformatics data.FindingsWe identified 1162 genes that had a normalized expression after treating the mice with drugs proven effective in preclinical models. Intersecting these genes with target affinity profiles for clinically-approved drugs in ChEMBL, resulted in the identification of 116 drugs targeting 29 proteins, of which several are previously linked to Polycystic Kidney Disease such as Rosiglitazone. Further testing the efficacy of six candidate drugs for inhibition of cyst swelling using a human 3D-cyst assay, revealed that three of the six had cyst-growth reducing effects with limited toxicity.InterpretationOur data further establishes drug repurposing as a robust drug discovery method, with three promising drug candidates identified for ADPKD treatment (Meclofenamic Acid, Gamolenic Acid and Birinapant). Our strategy that combines multiple-omics data, can be extended for ADPKD and other diseases in the future.FundingEuropean Union's Seventh Framework Program, Dutch Technology Foundation Stichting Technische Wetenschappen and the Dutch Kidney Foundation.

Highlights

Drug repurposing, defined as the application of known drugs and compounds to treat new indications, is seen as a bypass for the long and expensive process of developing new drugs
To study the different phases of Autosomal Dominant Polycystic Kidney Disease (ADPKD) progression, we have inactivated Pkd1 at postnatal day 38 or 90 in the kidneys and harvested these animals at different time points after gene inactivation, resulting in five groups of mice with different disease stages
Pkd1cko animals sacrificed at 11 and 12 weeks after gene inactivation represent a moderate state of the disease and Pkd1cko animals sacrificed at 15 weeks after gene inactivation represent advanced disease

Summary

Introduction

Drug repurposing, defined as the application of known drugs and compounds to treat new indications, is seen as a bypass for the long and expensive process of developing new drugs. Autosomal Dominant Polycystic Kidney Disease (ADPKD) is one of the most common causes of end-stage renal failure, caused by mutations in PKD1 or PKD2 genes. Methods: In this study, we applied RNA-sequencing of Pkd1cko mice at different disease stages, and with/ without drug treatment to identify genes involved in ADPKD progression that were further used to identify novel drug candidates for ADPKD. Findings: We identified 1162 genes that had a normalized expression after treating the mice with drugs proven effective in preclinical models. Intersecting these genes with target affinity profiles for clinicallyapproved drugs in ChEMBL, resulted in the identification of 116 drugs targeting 29 proteins, of which several are previously linked to Polycystic Kidney Disease such as Rosiglitazone.

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