Placental nanoparticle gene therapy normalizes gene expression changes in the fetal liver associated with fetal growth restriction in a fetal sex-specific manner

Abstract

Fetal growth restriction (FGR) is associated with increased risk of developing Non-Communicable Diseases. We have a placenta-specific nanoparticle gene therapy protocol that increases placental expression of human insulin-like growth factor 1 (hIGF-1), for the treatment of FGR in utero. We aimed to characterize the effects of FGR on hepatic gluconeogenesis pathways during early stages of FGR establishment, and determine whether treatment of the placenta with nanoparticle mediated hIGF-1 therapy could resolve differences in the FGR fetus. Female Hartley guinea pigs (dams) were fed either a control or maternal nutrient restriction (MNR) diet using established protocols. At GD30-33, dams underwent ultrasound guided, transcutaneous, intra-placental injection of hIGF-1 nanoparticle or PBS (sham), and were sacrificed 5 days post-injection. Fetal liver tissue was fixed and snap frozen for morphology and gene expression analysis. In female and male fetuses, liver weight as a percentage of body weight was reduced by MNR, and not changed with hIGF-1 nanoparticle treatment. In female fetal livers, expression of hypoxia inducible factor 1 (Hif1) and tumor necrosis factor (Tnf) were increased in MNR compared to Control, but reduced towards Control in MNR + hIGF-1 livers. In male fetal liver, MNR increased expression of Igf-1, and decreased expression of Igf-2 compared to Control. Igf-1 and Igf-2 expression was restored to Control levels in the MNR + hIGF-1 group. This data provides further insight into the sex-specific mechanistic adaptations seen in FGR fetuses, and demonstrates that disruption to fetal developmental mechanisms may be returned to normal by treatment of the placenta.