A novel system for rational discovery of polycystic kidney disease therapeutics

Polycystic kidney disease (PKD) is the most frequent life-threatening genetic disease, affecting almost 1 million people in the US alone. It is characterized by growth of numerous cysts that progressively replace normal kidney tissue, which eventually leads to kidney failure, requiring chronic dialysis or transplantation. Currently without treatment, PKD constitutes a very large unmet medical need. PKD is caused by inhibitory mutations in PKD1 or PKD2, two interacting membrane proteins that activate a poorly understood signal transduction pathway (hereby, the PKD pathway) that is normally required for suppressing cyst formation. An attractive therapeutic strategy would be to rescue signaling activity downstream of defective PKD1 and PKD2. A major barrier has been the lack of a tractable system for dissecting the PKD pathway. We have recently developed a robust cell-based system that recapitulates PKD signaling, which allows, for the first time, rapid and quantitative measurements of PKD signaling, in a manner not possible in more complicated animal or tissue models. Currently, we are using this powerful system to comprehensively identify and dissect PKD pathway components. Here, we propose to use this novel system to discover small molecules capable of correcting defective signaling in PKD.