Kidney Week

Abstract: FR-PO487

Identification and In Vitro Characterisation of a Novel Inhibitor of Vascular Calcification

Session Information

• Bone and Mineral Metabolism: Basic
  October 26, 2018 | Location: Exhibit Hall, San Diego Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Bone and Mineral Metabolism

• 401 Bone and Mineral Metabolism: Basic

Authors

• Schantl, Antonia Elisabeth, ETH Zurich, Zurich, Switzerland

Antonia Elisabeth Schantl,

• Ivarsson, Mattias E., Inositec Inc., Zurich, Switzerland

Mattias E. Ivarsson,

• Castagner, Bastien, McGill University, Montreal, Quebec, Canada

Bastien Castagner,

• Leroux, Jean-Christophe, ETH Zurich, Zurich, Switzerland

Jean-Christophe Leroux,

Background

Vascular calcification (VC) is the pathological deposition of calcium and phosphate minerals in the walls of the cardiovascular system. At present, there is no approved pharmacological treatment and affected individuals are left at great risk of experiencing cardiovascular events and death. Herein, we describe a new class of inhibitors of VC based on the previously reported inhibitor myo-inositol hexaphosphate (IP6), with improved drug-like properties.

Methods

Multi-step syntheses, starting from protected myo-inositol species, via selective PEGylation, phosphorylation or sulfation were employed to afford a library of novel IP6 derivatives. Activity was compared in a serum calcification propensity assay, and stability was monitored in serum. In vitro efficacy experiments were performed on primary human vascular smooth muscle cells (VSMCs), treated with either calciprotein particles (CPPs) (50 μg/mL) or calcification medium (2.7 mM calcium and 2.5 mM phosphate, CaP), respectively. Subsequently, calcification of the cell monolayer, cell viability and expression of cell markers were assessed.

Results

Synthesis and screening of twelve monodispersed PEGylated IP6 derivatives revealed IP4-di-PEG₂ (INS-3001) to be almost 10-fold more potent than IP6 in delaying serum calcification propensity, with activity in the low μM range. This activity was retained following 4 h incubation in fresh human serum. VSMC calcification was largely abolished by 1 μM INS-3001 in the CaP setup (Figure 1), and 30 μM INS-3001 in the CPP setup, respectively.

Conclusion

INS-3001 was superior to natural IP6 with regard to serum calcification propensity, in vitro stability and efficacy in cell culture models. Thus, the presented in vitro data provides support for the further development of INS-3001 as an inhibitor of vascular calcification.

Figure 1 Reduction of VSMC calcification by INS-3001.

Funding

• Commercial Support –