1024: hu-IGF-1 nanoparticle placental injection for fetal growth restriction treatment is safe

Abstract

We previously demonstrated nanoparticle mediated trophoblast-specific Hu-IGF-1 expression increased placental nutrient transport to maintain fetal growth in a surgically induced mouse model of fetal growth restriction (FGR, Jones, 2015). Modelling FGR in a guinea pig permits a longer gestation for developing treatment of pre-existing FGR (Roberts, 2018). Our aim was to investigate mechanisms of fetal programming in FGR in Guinea pigs and assess the impact of nanoparticle mediated transgene delivery. Control dams (n=5) received chow ad Libitum while the maternal nutrient restricted (MNR) group (n=3) received 70% preconception diet through mid-gestation which increased to 90% ad Libitum from 30 d.p.c. through necropsy. Pregnancy was confirmed by transabdominal ultrasound on 21 d.p.c. Tran-placental injection of nanoparticles (HPMA-DMAEMA:PLAC1Hu-IGF1 or HPMA-DMAEMA:CYP19Hu-IGF1) was performed at 30-36 d.p.c under ultrasound guidance. Dams were sacrificed 5 days post-injection, and maternal, placental and fetal demographics collected. Fetal organs were harvested and processed for expression analysis. Whole RNA isolation was performed and TGF-β, TNF-α, CTGF, and MMP-2 RNA expression was analyzed by qPCR in fetal liver, heart, and brain. To assess proliferation and vessel density immunohistochemistry was performed with anti-Ki67 and anti-CD31 antibodies on fetal liver and heart. Fetal weight, organ size and glucose was significantly reduced in restricted compared to control offspring with brain sparing in the restricted group (Table 1). TGFβ in fetal restricted heart increased 1 fold over controls (P< 0.5) and 4.5 fold in brain (P< 0.01). CTGF increased 1.5 fold (P< 0.05) in fetal brain with no alteration in TNFα or MMP-2 (Figure 1). Despite reduced organ weights, proliferation (Ki-67) rates and vascular (CD31) were similar between controls and MNR in the fetal heart and liver. Our model recapitulates FGR with brain sparing and initial experiments with NP-IGF-1 demonstrate no detrimental impact to fetal growth and development in normal pregnancy.View Large Image Figure ViewerDownload Hi-res image Download (PPT)