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Kidney Week

Abstract: FR-PO736

3D In Vitro Cystogenesis Assays Utilizing Human Patient-Derived ADPKD Kidney Cells for Drug Screening

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic


  • Redmann, Matthew, DiscoveryBioMed, Inc., Birmingham, Alabama, United States
  • Zarkin-Scott, Shaina, DiscoveryBioMed, Inc., Birmingham, Alabama, United States
  • Schwiebert, Erik Mills, DiscoveryBioMed, Inc., Birmingham, Alabama, United States
  • Mai, Deborah, DiscoveryBioMed, Inc., Birmingham, Alabama, United States

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is a slowly progressive genetic renal disorder that is caused by mutations in either the PKD1 gene (polycystin 1) or the PKD2 gene (polycystin 2). ADPKD is characterized by the formation of fluid filled cysts in both kidneys leading eventually to end-stage renal disease. Several in vivo and in vitro models of ADPKD exist, although many of them fall short of fully recapitulating the human disease phenotype, driving the failure of most therapeutic candidates in human clinical trials.


We have developed a unique 3D Biogel-based platform in 384-well tissue culture format utilizing cells isolated from individual cysts on human ADPKD donor kidneys. Cultures from each individual cyst are genotyped to determine the PKD1 or PKD2 mutation. Interestingly, from 9 human ADPKD donor tissues to date (8 with PKD1 mutations, 1 with a PKD2 mutation), we have discovered that only a subset of donors are prone to second somatic hits in single cyst-derived cultures, in addition to the germline mutation. These cells form cysts over days to weeks in culture that can be tracked by high-content imaging with cyst size and number being quantified through algorithm-based image analysis. This platform can be used for screening or validation of candidate drugs and provides significant advancement in throughput and pathophysiologic relevancy.


Here, we show the effects of proprietary small molecules derived from a pre-clinical Cystic Fibrosis (CF) drug discovery program. In human bronchial epithelial cells, these compounds confer a dual effect of CFTR correction and ENaC inhibition. In our system, they are capable of reducing both the size and total number of cysts present after more than a week in culture.


The exact mechanism of action remains to be elucidated, but our data suggests two key findings. First, primary cultures of human cyst cells can be derived from individual cysts of ADPKD kidney tissues and can form cysts in 3D Biogel in a medium-throughput screening system to profile candidate PKD therapeutics. Second, treatments once reserved for CF and other genetic diseases might open new avenues for treatments of PKD.

DBM acknowledges the Mayo Clinic PKD Center Genotyping Core for genotyping services.


  • NIDDK Support