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

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 ( Hif1α ) and tumor necrosis factor ( Tnfα ) 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.