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Abstract: PO0635

In Vivo Data to Support Induced Pluripotent Stem Cell-Derived Renal Progenitors as Potential Cell Therapy for Kidney Disease

Session Information

Category: Development, Stem Cells, and Regenerative Medicine

  • 500 Development, Stem Cells, and Regenerative Medicine

Authors

  • Woollard, Kevin, AstraZeneca UK Ltd, Cambridge, United Kingdom
  • Gruber, Ralph, AstraZeneca UK Ltd, Cambridge, United Kingdom
  • Jonebring, Anna, AstraZeneca UK Ltd, Cambridge, United Kingdom
  • Svensson, Anna Kristina, AstraZeneca UK Ltd, Cambridge, United Kingdom
  • Liarte Marin, Elena, AstraZeneca UK Ltd, Cambridge, United Kingdom
  • Dahlqvist, Ulrika, AstraZeneca UK Ltd, Cambridge, United Kingdom
  • Hicks, Ryan, AstraZeneca UK Ltd, Cambridge, United Kingdom
  • Laerkegaard Hansen, Pernille B., AstraZeneca UK Ltd, Cambridge, United Kingdom

Group or Team Name

  • Bioscience Renal, Early CVRM, BioPharmaceuticals R&D
Background

Novel therapies are needed to deliver life changing medicines to renal patients and cell therapy is a relatively new strategy of kidney therapy. We have developed novel methodology to produce kidney organoids for target validation. Here we have used this learning, to derive human renal progenitor cells (RPC) and examine their differentiation in-vivo using 2 delivery models

Methods

We used iPSC modified to contain a GFP reporter of nephrin expression, to generate human RPC differentiated to day 6 and 10 using a previously described kidney organoid protocol. We then used kidney capsule implantation and intravenous delivery in naïve and Ischemia/Reperfusion Injury (IRI) NOD/SCID background mice respectively. For kidney capsule, we compared RPC implantation number (3 and 5x106) and time (1 and 5 weeks). For IRI, we infused i.v RPC (5x106) directly after kidney clamping (24mins)/reperfusion and measured systemic biodistribution of RPC at 2 and 25 days. Other readouts included kidney human RNAseq, renal function, plasma cytokines and histology

Results

We can currently show RPC implanted in kidney capsule continue differentiation towards mature renal cell types. Using histology and hRNA signatures, there is some enrichment towards tubular like cells particular at high dose, using day 10 matured progenitors at 5 weeks after implantation. These include differentiation of tubular transporters, such as nucleoside (ENT1) and water-transporting proteins (AQP1). In IRI experiments, i.v infusion was well tolerated with normal disease course based on increases in plasma creatinine, BUN and urinary KIM-1. Biodistribution and differentiation analysis is underway, focused on anti-human nuclear staining in multiple organs and qPCR. Plasma inflammatory, cardiac and renal biomarkers analysis will examine any RPC infiltrate response

Conclusion

These observations clearly demonstrate the use and differentiation potential of RPC in a pre-clinical setting. These studies may aid design and delivery modality, for any future effort in examining RPC therapy for renal disease

Funding

  • Commercial Support – AstraZeneca