Human Organoids as Drug Development Tools for Polycystic Kidney Disease

Polycystic kidney disease (PKD) is commonly inherited as a loss-of-function mutation in PC1 (polycystin-1) or PC2. The molecular functions of polycystins remain uncertain, and therapeutics remain limited for millions of patients. One major roadblock has been the scarcity of assays that re-create PKD-specific cystogenesis in vitro, to complement mouse models. Over the past decade, a human organoid model of PKD has emerged that promises to bridge this gap. Human kidney organoids derived from PKD1-/- or PKD2-/- pluripotent stem cells recapitulate the pathognomonic cystic phenotype in a PKD-specific manner. This system reveals that PKD cystogenesis is a cell intrinsic process that can be re-created in vitro. Human PKD organoids have revealed unexpected mechanisms for PKD cystogenesis, and have been utilized to blueprint new therapeutic strategies, but their potential is not yet fully realized. The complexity and cost of organoids remain significant barriers to entry, and dedicated technology development is required to improve their physiological relevance. Here we review important achievements, current limitations, and future strategies, with a focus on translational 'bench to bedside' potential of PKD organoids as drug development tools.