Biopolymer-Delivered, Maternally Sequestered NF-κB (Nuclear Factor-κB) Inhibitory Peptide for Treatment of Preeclampsia

Abstract

Preeclampsia is a hypertensive disorder of pregnancy that causes significant acute and long-term risk to the mother and the baby. The multifaceted maternal syndrome is driven by overproduction of circulating anti-angiogenic factors, widespread inflammation, and endothelial dysfunction. Nuclear factor-κB (NF-κB) is a transcription factor that plays a central role in the inflammatory response. Its activity is increased in the preeclamptic placenta, and it promotes the systemic endothelial dysfunction present in preeclampsia. There is an acute need for new therapeutics targeted to the causative pathways of preeclampsia. Our group has developed a drug delivery system based on the bioengineered protein ELP (elastin-like polypeptide) that is capable of stabilizing therapeutics in the maternal circulation and preventing their placental transfer. Here we used the ELP carrier system to deliver a peptide known to inhibit the NF-κB pathway. This polypeptide, containing a cell-penetrating peptide and an NF-κB inhibitory peptide derived from the p50 nuclear localization sequence (abbreviated SynB1-ELP-p50i), blocked NF-κB activation and prevented TNF-α (tumor necrosis factor alpha)–induced endothelin production in vitro. Fusion of the p50i peptide to the SynB1-ELP carrier slowed its plasma clearance and prevented its placental transfer in pregnant rats, resulting in increased deposition in the maternal kidney, liver, and placenta relative to the free peptide. When administered in a rat model of placental ischemia, SynB1-ELP-p50i partially ameliorated placental ischemia-induced hypertension and reduced placental TNF-α levels with no signs of toxicity. These data support the continued development of ELP-delivered NF-κB inhibitors as maternally sequestered anti-inflammatory agents for preeclampsia therapy.

The Role of NF-κB in Uterine Spiral Arteries Remodeling, Insight into the Cornerstone of Preeclampsia

“…Therefore, inhibition of this pathological inflammatory response with drugs with non- or low penetration into the foetal part of placenta and blood probably would reduce the risk of disturbance of beneficial NF-κB mediated processes and would ameliorate maternal symptoms. Eddy et al created an elastin-like polypeptide (ELP), associated it with NF-κB inhibitor p50i, and administered it to pregnant rats [ 78 ]. Fusion of p50i with ELP prevented its placental transfer in pregnant rats, resulting in increased deposition in the maternal kidney, liver, and placenta relative to the free peptide [ 78 ].…”

“…Eddy et al created an elastin-like polypeptide (ELP), associated it with NF-κB inhibitor p50i, and administered it to pregnant rats [ 78 ]. Fusion of p50i with ELP prevented its placental transfer in pregnant rats, resulting in increased deposition in the maternal kidney, liver, and placenta relative to the free peptide [ 78 ]. Furthermore, in a rat model of placental ischemia, ELP-p50i partially ameliorated placental ischemia-induced hypertension and reduced placental TNF-α levels with no signs of toxicity [ 78 ].…”

Recovery of Renal Function following Kidney-Specific VEGF Therapy in Experimental Renovascular Disease

“…Furthermore, although we showed that the KTP-ELP construct and the fusion of KTP-ELP-VEGF target the kidney independent of the species tested [17, 18], additional studies in the swine model of RVD would be needed to characterize its biodistribution, targeting profile, and safety, as we did with ELP-VEGF [10, 11]. Still, it is important to highlight that the current study supports the plasticity of ELP technology to be fused to different therapeutic agents [10, 11, 49] as well as the possibility of applying ELP-driven strategies in other diseases [49] and in other forms of renal disease [12, 50] which offers the opportunity for more avenues of needed research towards new applications and for the progression of its potential for clinical translation.…”

Differential regulation of sFlt-1 splicing by U2AF65 and JMJD6 in placental-derived and endothelial cells

“…Sham animals were incised, and vessels isolated as above, but no clips were placed. Additionally, mean arterial pressure measurements were performed on GD 19 via carotid catheter indwelling, as previously described [21] (data not shown). Animals were subsequently euthanized by isoflurane overdose, pneumothorax, and cardiac excision.…”