New therapeutic strategy against preeclampsia : Angiogenic switch to Physiological state by Extracorporeal Removal of sFlt1 and release of free PlGF – APHERESE
Preeclampsia is a hypertensive disorder of pregnancy associated with important maternal and perinatal mortality and morbidity. 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 2500 g. 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 defective remodeling of the uterine vascularization. This results progressively in placental hypoperfusion, which induces trophoblast dysfunction and the release in maternal circulation of trophoblastic factors leading to an excessive inflammatory response, endothelial dysfunction and glomerular damage. Among these factors, the most important 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 receptor. The result is inhibition of the effects of VEGF and PlGF on maternal endothelial cells and podocytes. The sFlt-1/PlGF ratio reflects the circulating angiogenic balance and is correlated with severity of the disease.
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. The alternative is to eliminate from the maternal circulation the placenta-derived sFlt-1 produced in excess. We therefore aim to develop a specific apheresis system to reduce circulating sFlt-1 and to increase free PlGF in order to restore the physiologic angiogenic balance that maintains a healthy endothelial function and normal glomerular stage. To shift the equilibrium of sFlt-1/PlGF binding, we envisage grafting the capture surface of magnetic beads with molecules that behave as a competitive antagonist of PlGF in its binding to sFlt-1 and have a greater affinity than PlGF for sFlt-1 (VEGF the natural ligand, synthetic peptides and peptidomimetic ligands are potential candidates). This competitive biomimetic binding approach will capture the circulating sFlt-1 while releasing PlGF from its soluble receptor and will modulate the sFlt-1/PlGF ratio more effectively, thereby increasing the bioavailability of PlGF and potentiating its effects on maternal endothelial function.
For this proof of concept, we will also use a new approach based on fluidized bed. This microfluidic technology enhances mass transfer between the solid and liquid phases and should therefore improve the restoration of the physiological sflt1/PlGF ratio compared to conventional apheresis systems.
Monsieur Vassilis Tsatsaris (Hopital Cochin)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
UPD - COMETE Laboratoire Chimie organiqie Médicinale et Extractive et Toxicologie Expérimentale
PREMUP FCS PREMUP
CURIE INSTITUT CURIE - SECT DE RECHERCHE
PREMUP INSERM UMR 1139 FONDATION PREMUP
Hopital Cochin Hopital Cochin
Help of the ANR 418,802 euros
Beginning and duration of the scientific project: September 2016 - 36 Months