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

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