. Preeclampsia is a common hypertensive disorder of pregnancy and is one of the leading causes of maternal, fetal, and perinatal morbidity and mortality. Affecting ~8% of all pregnancies in the US, preeclampsia displays characteristic hypertension, proteinuria, and altered cardiovascular function and, if left unchecked, can lead to maternal seizures and death. There is currently no effective intervention for preeclampsia short of induced delivery of the fetus, which is why it is also a leading cause of premature birth. Improvements in preeclampsia management have been largely stifled due to deleterious effects of various proposed small- molecule therapeutics on the developing fetus. The objective of the proposed studies is to develop a drug delivery system capable of stabilizing novel therapeutic agents in the maternal circulation while protecting them from entering the fetal circulation. The onset and progression of preeclampsia is driven by two major pathways, secretion of the VEGF antagonist sFlt-1 and induction of a highly inflammatory environment in the mother. We have developed two novel agents targeting each of these pathways, a supplementary VEGF therapy to counteract the increased sFlt-1 levels and an NF-?B inhibitory peptide therapy to block the inflammatory response. These therapeutics are attached to a drug delivery vector called elastin-like polypeptide (ELP) that stabilizes them in the maternal circulation while preventing them from crossing the placenta into the fetal circulation.
The aims of this proposal are to 1) assess the pharmacokinetics, biodistribution, placental targeting, and fetal exclusion of several iterations of this drug carrier, 2) evaluate the in vitro mechanisms and in vivo efficacy of the ELP-VEGF therapeutic in a rat preeclampsia model, 3) evaluate the in vitro mechanisms and in vivo efficacy of the ELP-fused NF-?B inhibitory therapeutic in a rat preeclampsia model, and 4) assess the development of hypertension in the offspring of preeclamptic mothers treated with these test agents. !

Public Health Relevance

Preeclampsia is a hypertensive disorder of pregnancy that is a leading cause of morbidity and mortality in both the mother and infant, and there is currently no cure other than delivery of the fetus and the placenta. This proposal will test a protein-based drug carrier for delivery of novel protein and peptide therapeutics targeted to pathways important for preeclampsia. This delivery system targets therapeutic proteins at high levels in the placenta while preventing therapeutics from entering the fetal circulation.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL121527-01
Application #
8613787
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Mitchell, Megan S
Project Start
2014-01-15
Project End
2018-12-31
Budget Start
2014-01-15
Budget End
2014-12-31
Support Year
1
Fiscal Year
2014
Total Cost
$336,375
Indirect Cost
$111,375
Name
University of Mississippi Medical Center
Department
Neurology
Type
Schools of Medicine
DUNS #
928824473
City
Jackson
State
MS
Country
United States
Zip Code
39216
Bidwell 3rd, Gene L; George, Eric M (2014) Maternally sequestered therapeutic polypeptides - a new approach for the management of preeclampsia. Front Pharmacol 5:201
George, Eric M; Liu, Huiling; Robinson, Grant G et al. (2014) A polypeptide drug carrier for maternal delivery and prevention of fetal exposure. J Drug Target 22:935-47