Abstract: SA-OR053
An iPSC platform for Human Preclinical Evaluation of Kidney Disease Targeting Compounds
Session Information
- Glomerular Diseases: Technologies, Mechanisms, and Therapeutics
November 09, 2019 | Location: 201, Walter E. Washington Convention Center
Abstract Time: 05:30 PM - 05:42 PM
Category: Glomerular Diseases
- 1204 Podocyte Biology
Authors
- Westerling-Bui, Amy Duyen, Goldfinch Bio, Inc., Cambridge, Massachusetts, United States
- Soare, Thomas, Goldfinch Bio, Inc., Cambridge, Massachusetts, United States
- Zhang, Wei, Goldfinch Bio, Inc., Cambridge, Massachusetts, United States
- Venkatachalan, Srinivasan, Goldfinch Bio, Inc., Cambridge, Massachusetts, United States
- Emani, Maheswarareddy, Broad institute of MIT and Harvard, Cambridge, Massachusetts, United States
- Fanelli, Alyssa, Goldfinch Bio, Inc., Cambridge, Massachusetts, United States
- Murray, Evan, Goldfinch Bio, Inc., Cambridge, Massachusetts, United States
- Corriea, Grinal M., Goldfinch Bio, Inc., Cambridge, Massachusetts, United States
- Hoang, Hien G., Goldfinch Bio, Inc., Cambridge, Massachusetts, United States
- Kyrychenko, Sergii, Goldfinch Bio, Inc., Cambridge, Massachusetts, United States
- Yu, Maolin, Goldfinch Bio, Inc., Cambridge, Massachusetts, United States
- Daniels, Matthew, Goldfinch Bio, Inc., Cambridge, Massachusetts, United States
- Malojcic, Goran, Goldfinch Bio, Inc., Cambridge, Massachusetts, United States
- Pan-Zhou, Xin-Ru, Goldfinch Bio, Inc., Cambridge, Massachusetts, United States
- Tibbitts, Thomas T., Goldfinch Bio, Inc., Cambridge, Massachusetts, United States
- Harmange, Jean-Christophe, Goldfinch Bio, Inc., Cambridge, Massachusetts, United States
- Reilly, John F., Goldfinch Bio, Inc., Cambridge, Massachusetts, United States
- Mundel, Peter H., Goldfinch Bio, Inc., Cambridge, Massachusetts, United States
Group or Team Name
- Goldfinch Bio
Background
A major challenge in drug target validation and assessment of efficacy is the limited translation between preclinical animal models and human diseases, which is often invoked to explain the failure of investigational drugs to produce the expected therapeutic benefit. Human iPSC-derived cells and organoids offer an opportunity to complement preclinical animal models, but their systematic use remains challenging due to the technical complexity associated with consistent cell culture and scalability.
Methods
Here, we report a robust, reproducible and scalable platform for generating iPSC derived human podocytes and kidney organoids to enable target validation and preclinical assessment of therapeutic agents targeting the kidney. The organoid platform was characterized by immunofluorescence analysis of kidney differentiation markers and by assessing transcriptomic changes during organoid differentiation in vitro and following in vivo transplantation under the rat kidney capsule using single-cell RNA sequencing.
Results
Here, we report three examples supporting the use of these models by – a) providing a mechanistic basis for the antiproteinuric effects of cyclosporine A via protective effects on podocytes from Rac1-mediated cytoskeletal injury in vitro, b) exploring of the effects of disease-causing genetic mutations, and c) demonstrating the protective effect of a novel TRPC5 channel blocker, GFB-887. In vivo transplantation resulted in vascularization of human iPSC derived kidney organoids, with functional perfusion confirmed by pharmacokinetic measurement of GFB-887 in the organoid after dosing by oral gavage.
Conclusion
Our kidney disease-targeted human iPSC platform provides a valuable complement to pre-clinical models for target validation and assessment of drug efficacy.