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Abstract: FR-PO486

INS-3001 Efficiently Inhibits Severe Vascular Calcifications by Direct Interference with Vessel Wall Calcification

Session Information

Category: Bone and Mineral Metabolism

  • 401 Bone and Mineral Metabolism: Basic

Authors

  • Verhulst, Anja, University of Antwerp, Antwerp, Antwerp, Belgium
  • Ivarsson, Mattias E., Inositec Inc., Zurich, Switzerland
  • Maj, Roberto, Inositec AG, Zurich, Switzerland
  • Neven, Ellen, University of Antwerp, Wilryk, antwerp, Belgium
  • D'Haese, Patrick C., University Antwerp, Edegem, Belgium
Background

Prevention/treatment of vascular calcification currently is based on controlling its most important risk factors. A new therapeutic approach with potential higher efficacy consists in the administration of molecules directly interfering with the calcification process in the vessel wall, such as INS-3001. This abstract reports about the administration of INS-3001 in a rat model of vitamin D-warfarin induced vascular calcifications (pooled data of 3 independent studies).

Methods

Calcification was induced in male rats (8 weeks) by warfarin (3mg/g diet) administration during 6 days and by 4 consecutive daily administrations of vitD3 (100.000 IU/kg) starting on day 1 of the warfarin administration. Rats were randomly assigned to different groups: vehicle, and INS-3001 groups of 12, 25, 2x25, 50 and 2x50 mg/kg/day. Treatment was administrated sc. for 7 days (starting together with vitD). Animals were sacrificed on the 8th day. Vascular calcification was evaluated on Von Kossa stained tissue sections of the thoracic/abdominal aorta and by measurement of the total Ca content of the thoracic/abdominal aorta and the carotid/femoral arteries by atomic absorption spectrometry.

Results

Mortality rate was 38% (15/40) in the vehicle group, similar -33% (4/12) and 44% (5/12)- in the 1x25 and 1x12.5 mg/kg/day dose groups, numerically lower -15% (3/19), 21% (4/19)- in the 2x50, 1x50 mg/kg/day dose groups and significantly lower 0% (0/18) in the 2x25 mg/kg/day dose group. In the abdominal aorta, significantly lower Von Kossa positivity (area%) was measured in the INS-3001 groups compared to the vehicle group (3±5%, 6±4%, 8±7%, 15±3%, 20±3% and 28±10% in respectively the 2x50, 50, 2x25, 25, 12.5 mg/kg/day and the vehicle group). Total Ca content of the abdominal aorta was also significantly lower in the INS-3001 (not the 12.5 and 25 mg/kg/day) groups compared to the vehicle group (2.8±3.7, 6.1±5.0, 7.4±6.9, 14.9±7.0, 15.6±9.4 and 14.9±7.5 mg/g tissue in respectively the 2x50, 50, 2x25, 25, 12.5 mg/kg/day and the vehicle group. Similar reductions in area% Von Kossa positivity and total Ca content were seen in the thoracic part of the aorta, and the arteria femoralis and carotis.

Conclusion

In conclusion, INS-3001 is a promising molecule for the treatment of CKD and non-CKD induced vascular calcifications.

Funding

  • Commercial Support