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Abstract: FR-PO529

Inositol Phosphate Analogs as Inhibitors of Renal Calcium Oxalate Crystallization

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Kletzmayr, Anna, ETH Zurich, Zurich, Switzerland
  • Ivarsson, Mattias E., Inositec Inc., Zurich, Switzerland
  • Castagner, Bastien, McGill University, Montreal, Quebec, Canada
  • Leroux, Jean-Christophe, ETH Zurich, Zurich, Switzerland

Group or Team Name

  • Drug Delivery and Formulation
Background

Nephrocalcinosis and nephrolithiasis can be triggered by calcium oxalate (CaOx) crystallization, a main symptom in different forms of hyperoxaluria. To date, treatment options for pathologies involving renal CaOx crystallization are scarce, mostly aiming at slowing down disease progression, rather than directly targeting crystal growth and deposition. Inositol hexaphosphate (IP6) was previously shown to inhibit crystallization of calcium salts. Its clinical use, however, may be hampered by its low urine exposure following parenteral dosing. In this project, we aim at developing inhibitors against renal CaOx crystallization, based on IP6 analogs.

Methods

Potency of compounds to inhibit CaOx crystallization was assessed by light scattering measurements. Effects on the CaOx crystal morphology were characterized by light microscopy, followed by an automated image analysis and machine learning approach to classify different CaOx hydrate forms. In vitro cell experiments were performed using RPTEC human proximal tubular cells. Adhesion of CaOx crystals to a cell monolayer was determined by light microscopy and CaOx induced cellular toxicity in vitro was measured with a viability stain.

Results

In the initial screening of a small library of IP6 analogs, a subgroup of compounds that included IP5-mono-PEG2 (INS-2001), showed inhibitory potential in the low micromolar range. Light microscopy experiments performed in human urine, confirmed the dose-dependent reduction in size of CaOx monohydrate crystals upon the addition of INS-2001. This compound also significantly reduced CaOx adhesion to renal epithelial cells at submicromolar concentrations. Additionally, protective effects of INS-2001 on CaOx induced cellular toxicity in vitro were observed.

Conclusion

The data generated with INS-2001 provide a starting point for further optimization of the IP6 analogs for treatment of renal CaOx crystallization. In subsequent steps, inhibitory effects of INS-2001 and related compounds on CaOx-induced fibrosis and inflammation in vitro, and in vivo efficacy will be characterized in depth.

Funding

  • Government Support - Non-U.S.