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Kidney Week

Abstract: FR-PO583

Identification of Novel Targets for Autosomal Dominant Polycystic Kidney Disease Using a Patient Cell-Derived Cyst Model

Session Information

Category: Genetic Diseases of the Kidneys

  • 1201 Genetic Diseases of the Kidneys: Cystic

Authors

  • Feaver, Ryan E., HemoShear Therapeutics, Charlottesville, Virginia, United States
  • Cole, Banumathi K., HemoShear Therapeutics, Charlottesville, Virginia, United States
  • Pourtaheri, Taylor, HemoShear Therapeutics, Charlottesville, Virginia, United States
  • Hoang, Steve A., HemoShear Therapeutics, Charlottesville, Virginia, United States
  • Lawson, Mark J., HemoShear Therapeutics, Charlottesville, Virginia, United States
  • Velthuisen, Emile, HemoShear Therapeutics, Charlottesville, Virginia, United States
  • Johns, Brian, HemoShear Therapeutics, Charlottesville, Virginia, United States
  • Figler, Robert A., HemoShear Therapeutics, Charlottesville, Virginia, United States

Group or Team Name

  • HemoShear Therapeutics, Inc.
Background

Autosomal dominant polycystic disease (ADPKD) is the most common potentially lethal monogenic disorder and the most inherited kidney disease. Therapeutic development in ADPKD has been hampered by the lack of understanding of how mutations in polycystin 1 or 2 lead to uncontrolled cyst growth and ultimately end-stage renal disease.

Methods

We developed a 3-dimensional in vitro cyst model consisting of primary human epithelial cells derived from the cyst walls of ADPKD patients. The cells progressively form fluid-filled cysts within a collagen-rich gel in the span of 5-10 days and can be quantified through high-content imaging. To validate this model, a transcriptomic time course was obtained during cyst development and compared to transcriptomic signatures obtained from normal versus ADPKD biopsy tissue and secreted protein analysis of patient cyst fluid. Using data from these analyses, novel targets were assessed alongside established industry targets for their ability to inhibit cyst formation in the in vitro model.

Results

Comparing the transcriptomic signatures from the human in vitro model to patient tissue showed a high degree in overlapping responses and pathways that were consistent with the growth factors and chemokines confirmed to be present in patient cyst fluid. Clinical targets such as V2R, CFTR, and NRF2 showed varying effects in their ability to inhibit cyst formation. From our analysis, we hypothesized new targets based on the unbiased bioanalyses of the transcriptomic signatures, which showed equal or better inhibition of cyst formation in the model.

Conclusion

Mapping the response profile of over 50 therapeutic targets spanning diverse mechanisms of actions in the validated ADPKD patient-derived cyst model has enabled prioritization of key signaling hubs that may represent promising new therapeutic targets for ADPKD.