Abstract: TH-PO737
VEGF-Based Apheresis: A Targeted Therapy for Preeclampsia
Session Information
- Women's Health and Kidney Diseases
November 07, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Women’s Health and Kidney Diseases
- 2000 Women’s Health and Kidney Diseases
Authors
- Matin, Mahsa, Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
- Benzing, Thomas, CECAD, Cologne, Germany
- Schermer, Bernhard, CECAD, Cologne, Germany
- Hagmann, Henning, Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
Background
Preeclampsia is a pregnancy specific complication, occurring in 6 – 8 % of pregnancy cases and is the leading cause of 76,000 maternal and 500,000 prenatal deaths per year worldwide. Due to the current lack of effective treatment options and its high prevalence, developing an effective therapy for preeclampsia is of great importance. Based on the insight that elevated sFlt-1 plasma levels, by decoying VEGF and PlGF leads to preeclampsia, in the current study we set out to develop a highly specific sFlt-1 adsorption strategy to treat preterm preeclampsia.
Methods
According to in silico modeling a number of novel sFlt-1 ligand variants were generated and characterized by determination of equilibrium dissociation constant of the receptor binding affinity. The most affine candidates were chosen for immobilization on an optimized apheresis column. Binding efficiency, unspecifically bound proteins as well as release of VEGF and PlGF were analyzed in ex vivo experiments employing serum samples of patients with preeclampsia.
Results
We were able to successfully engineer an array of VEGF-variants with varying affinity to sFlt-1. One of them with a higher affinity to sFlt-1 than all its known isoforms. This VEGF molecule variant not only effectively captures sFlt-1, but additionally competes with and liberates both endogenous VEGF and PlGF. In experiments employing serum samples from 10 patients with preeclampsia this system yields 80% reduction of sFlt-1, while releasing around 85% PlGF and VEGF.
Conclusion
In this study we demonstrate a novel apheresis set up which enables adsorption of up to 80% of circulating sFlt1 with highest specificity, while further restoring angiogenic balance by liberating PlGF and VEGF. Our system is directly applicable for further testing in large animal models of preeclampsia, which is crucial to evaluate the effect of VEGF release on the pregnancy. In the future, our variants may allow for personalized and targeted therapy of preeclampsia at different stages of the disease.