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 (hIGF1), 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 placental nanoparticle-mediated hIGF1 therapy treatmentcould 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, intraplacental injection of hIGF1 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 hIGF1 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 in MNR + hIGF1 compared to MNR. In male fetal liver, MNR increased expression of Igf1 and decreased expression of Igf2 compared to Control. Igf1 and Igf2 expression was restored to Control levels in the MNR + hIGF1 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.