Kidney Week

Abstract: FR-PO1016

Modeling of FSGS in Podocin R138Q Knock-in iPSC-Derived Human Organoids

Session Information

• Genetic Diseases of the Kidneys: Non-Cystic - II
  October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidney

• 1002 Genetic Diseases of the Kidney: Non-Cystic

Authors

• Westerling-Bui, Amy Duyen, Goldfinch Bio, Cambridge, Massachusetts, United States

Amy Duyen Westerling-Bui,

• Cheng, Christina N., Goldfinch Bio, Cambridge, Massachusetts, United States

Christina N. Cheng,

• Fanelli, Alyssa, Goldfinch Bio, Cambridge, Massachusetts, United States

Alyssa Fanelli,

• Corriea, Grinal M., Goldfinch Bio, Cambridge, Massachusetts, United States

Grinal M. Corriea,

• Hoang, Hien G., Goldfinch Bio, Cambridge, Massachusetts, United States

Hien G. Hoang,

• Soare, Thomas, Goldfinch Bio, Cambridge, Massachusetts, United States

Thomas Soare,

• Tibbitts, Thomas T., Goldfinch Bio, Cambridge, Massachusetts, United States

Thomas T. Tibbitts,

• Harmange, Jean-Christophe P., Goldfinch Bio, Cambridge, Massachusetts, United States

Jean-Christophe P. Harmange,

• Mundel, Peter H., Goldfinch Bio, Cambridge, Massachusetts, United States

Peter H. Mundel,

Background

The recent development of iPSC derived human kidney organoids has opened the possibility to study human kidney physiology and pathophysiology in a differentiated, three-dimensional human experimental system in vitro. Organoids are an attractive approach to study genetic causes of human kidney diseases, such as FSGS. However, due to the fact that organoids are thought to represent second trimester human kidneys and due to lack of vascularization and urine flow, whether they can be used as a model system of human kidney diseases remains uncertain.

Methods

To explore whether FSGS can be reproducibly modeled in human iPSC-derived organoids, we generated CRISPR/Cas9-engineered podocin R138Q knock-in iPSCs and developed a protocol for their successful differentiation into human kidney organoids. The human podocin R138Q mutation was chosen in this proof-of-concept study because this variant causes FSGS with early disease onset and rapid progression to end-stage renal disease in patients and homologous R140Q causes FSGS in knock-in mice.

Results

Here we present a thorough characterization of R138Q organoids at the structural, molecular, cellular and pathophysiological level. We also present data on the phenotypic changes resulting from the treatment of organoids with pharmacologic agents.

Conclusion

We conclude that using iPSC-derived organoid technology is a promising tool for modeling human kidney disease, as it empowers ongoing drug discovery for genetically defined FSGS.

Funding

• Commercial Support –