Abstract 8: Delivery of an Anti-inflammatory NF-κB Inhibitory Polypeptide to Treat Preeclampsia
Preeclampsia is a hypertensive disorder of pregnancy that is a leading cause of maternal, fetal, and perinatal morbidity and mortality. There is currently no effective intervention for preeclampsia short of induced delivery of the fetus. Improvements in preeclampsia management have been largely stifled due to deleterious effects of proposed small-molecule drugs on the developing fetus. The 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. Our lab is developing therapeutics to target each of these pathways. To inhibit the maternal inflammatory response, we have developed an NF-κB inhibitory peptide therapy. This NF-κB inhibitory peptide is attached to a drug delivery vector called elastin-like polypeptide (ELP) that stabilizes it from rapid clearance and degradation in the maternal circulation while preventing it from crossing the placenta into the fetal circulation. When administered to pregnant rats on gestational day 14, ELP accumulated highly in the placenta but was barely detectable in the pups (placenta ELP levels were 17.9 fold higher than pup levels, p = 0.00058). The ELP-delivered NF-κB inhibitory peptide was highly active against the NF-κB pathway in human umbilical vein endothelial cells (HUVECs). TNFα stimulation led to NF-κB activation in HUVECs as evidenced by nuclear localization of the NF-κB p65 subunit (nuclear:cytoplasmic ratio increased from 0.76 to 1.79 after stimulation). This activation was completely blocked by pretreating the cells with the NF-κB inhibitory polypeptide (nuclear:cytoplasmic ratio of ~ 0.9 before and after TNFα stimulation), but not by a control polypeptide. Also, pretreatment of HUVEC cells with the NF-κB inhibitory polypeptide completely blocked TNFα stimulated endothelin-1 release from HUVECs, suggesting that this strategy will be effective for ameliorating pregnancy induced hypertension. The polypeptides had no effect on HUVEC proliferation. These results suggest that the ELP-delivered NF-κB inhibitory peptide is a strong inhibitor of the inflammatory response in vascular endothelial cells, is nontoxic, and can be delivered to the mother while being excluded from the fetus.
- © 2013 by American Heart Association, Inc.