A high-throughput drug-screen for new therapies in cystic kidney disease using a zebrafish model system

Aims: Cystic kidney disease is a common cause of chronic renal failure in children and adults with autosomal-dominant polycystic kidney disease (ADPKD) being a lot more common than autosomal-recessive polycystic kidney disease (ARPKD). Several syndromic diseases such as Meckel-Gruber-Syndrome and Bardet-Biedl-Syndrome are associated with cystic kidneys as well as Nephronophthisis/ Joubert-syndrome. Together, these diseases represent a significant health and economic burden and so far, depsite several promising approaches in mice using m-Tor inhibitors, CFTR-inhibitors, Vasopressin-inhbitors or TNF-alpha blockers the therapeutic benefits in humans have been unsatisfactory. As many pharmaceutical substances have unknown side effects other substances inhibiting progression of cystic kidney disease might already be on the market unrecognised.

Aim of this Study: In this study we use zebrafish as a model for a high-throughput drug screen to identify potential new therapeutic options in cystic kidney disease.

Results: So far, we have screened a library with 880 FDA-approved substances in zebrafish gene knockdown models using morpholino-injections for their ability to inhibit pronephric cyst formation and expansion and identified several groups of substances not previously known to inhibit cyst growth in different genetic knockdown models. Their mechanism of action is currently under investigation as well as their effect on kidney cysts in mammalian models.

Conclusion: Cystic kidney disease is a significant health problem and until today, there is no efficient therapy available. We successfully used zebrafish models for a high-throughput therapeutic substance screen and our results suggest common "end-pathways" in cyst formation despite different genetic origins of the cysts.

Drug screen - Kidney cyst - Zebrafish model