New therapeutics strategy against preeclampsia: Angiogenic switch to Physiological state by Extracorporeal Removal of sFLT-1 and release of PlGF – APHERESE2

Preeclampsia is a hypertensive disorder of pregnancy associated with important maternal and perinatal mortality. It complicates 2 to 7% of pregnancies and causes more than 70 000 maternal deaths each year worldwide. Although symptomatic management has improved there is currently no curative treatment, and only childbirth and delivery of the placenta, usually prematurely, alleviate the mother’s symptoms. The management of extremely preterm infants is a major societal challenge in medical, ethical and economic terms. Substantial advances in neonatology are enabling the intensive care of increasingly preterm infants (from 5.5 months of gestation), without really ensuring a neurologic and pulmonary outcome free of long-term handicap. These small for gestational age infants remain in a hospital setting until they attain a weight of approximately 2500g. The cost of their care is considerable. A study in the United Kingdom put the annual cost of care of such children, up to the age of 18 years, at over one billion euros. Therefore, the development of therapeutic strategies for preeclampsia is one of the highest priorities in perinatal medicine.
Placental insufficiency plays a central role in the pathophysiology of preeclampsia. Abnormal placentation during the first trimester leads to placental hypoperfusion, which induces trophoblast dysfunction and the release in maternal circulation of trophoblastic factors leading to the maternal symptoms. Among molecules that participate to the pathophysiology of preeclampsia, one of the most important players is sFLT-1, which is a soluble form of the VEGF and PlGF receptor. sFLT-1 binds to free VEGF and PlGF in the maternal circulation, thus reducing their bioavailability for their membrane receptors. Targeting the sFLT-1 pathway is one of the most promising strategies for the development of new treatments for preeclampsia. As sFLT-1 results from alternative splicing, its peptide sequence is identical to that of the extracellular part of the membrane receptor. The development of drugs that act specifically on the soluble form and not on the membrane form is therefore particularly complex. One solution is to eliminate from the maternal circulation the excess of placenta-derived sFLT-1 by extracorporeal epuration (apheresis) in order to restore the physiologic angiogenic balance. Plasmapheresis is a standard of care in many neurological, renal or hematological pathologies. During the APHERESE 1 project (ANR-15-CE17-0005), we were the first to establish the proof of concept that it is possible to capture the circulating sFLT-1 by its natural ligand (VEGF) while simultaneously releasing PlGF. Based on the same principle of capturing sFLT-1 with its natural ligand, but with significant improvements and innovations allowing greater specificity for sFLT-1 and efficiency of capture, our goal with the APHERESE 2 project is to develop a real apheresis column, as well as a rinsing method allowing its reutilization. The APHERESE 2 project is therefore the direct continuation of the APHERESE 1 project. This research, protected by patents, will be directly exploitable by a company for an application in human therapy. In order to carry out this project, a consortium made up of obstetric clinicians, cell biologists, biochemists and chemists with complementary capabilities has been set up.