#6189 PRECLINICAL VALIDATION OF REPURPOSABLE CANDIDATE DRUG COMPOUNDS FOR CYSTIC NEPHROPATHIES

Abstract

Abstract Background and Aims Early-onset cystic kidney disease is a clinically and genetically heterogeneous and overlapping group of rare and often severe disorders with limited, mostly symptomatic treatment options. We developed and utilized inherited polycystic cystic kidney disease (PKD) models to search for pharmacological agents that can rescue or mitigate the disease phenotype. Method A high-content screening platform for identification of chemical modifiers of cyst formation and progression in a zebrafish genetic cystic nephropathy model (IFT172 Morpholino-based knockdown in Tg(wt1b:eGFP)), using robotic microscopy with automated image classification and phenotype quantification was used to screen 1280 compounds from the Prestwick library for their cyst-inhibiting activity. Compounds with cyst-inhibitory efficacy and low toxicity in the Zebrafish and oral and trans-placental availability were selected for further study in two rodent PKD models, i.e. PCK and PKD/Mhm (cy/+) rats. Groups of 3-week-old homozygous PCK and heterozygous PKD/Mhm rats were administered orally for 10 weeks three candidate compounds, which included an antihistamine, an anthelmintic and an antifungal agent, or regular ROD16 chow (sick controls). In experimental week 5, blood was taken, and the kidneys were imaged sonographically under anaesthesia. In the last experimental week, glomerular filtration rate was determined by transcutaneous FITC-sinistrin injection. Masson trichrome staining was used to evaluate cyst formation in kidneys. Results 60 compounds with cyst preventive or cyst size reducing activity were identified in the zebrafish screening model. While one third of these compounds caused severe general toxicity, 12 of them showed medium and 4 strong cyst-inhibitory activity with no or mild off-target effects. These substances were from anthelminthic, antihistamine, antifungal and proton pump inhibitor drug classes. Preliminary results in the rodent models suggest that anthelminthic treatment reduced the number of cysts in female (3.3±1.3 vs. untreated control, 5.4±0.9) but not male PCK rats (3.7±0.6 vs. 3.9±0.7) after 10 weeks of treatment. These changes were accompanied by improved glomerular filtration rate (GFR) in treated females (t½: 0.22±0.04 min vs. 0.3±0 min). An improvement in GFR was also observed in female PKD/Mhm rats after 10 weeks of treatment with the anthelmintic compound compared to untreated control animals (t½: 0.24±0.06 vs. 0.51±0.16 min, p = 0.02). Conclusion Candidate cyst-inhibitory drugs identified in a zebrafish model were applied in rat models of PKD. The administration of an anthelmintic agent had a positive impact on the progression of polycystic kidney disease. The beneficial effect appears to be sex specific. If further corroborated, our findings may allow repurposing of a drug approved for another indication to slow disease progression in patients with cystic kidney diseases.