Placenta <i>hIGF1</i> nanoparticle treatment in guinea pigs mitigates FGR-associated fetal sex-dependent effects on liver metabolism-related signaling pathways

Fetal development in an adverse in utero environment significantly increases the risk of developing metabolic diseases in later life, including dyslipidemia, nonalcoholic fatty liver diseases, and diabetes. The aim of this study was to determine whether improving the in utero fetal growth environment with a placental nanoparticle gene therapy would ameliorate fetal growth restriction (FGR)-associated dysregulation of fetal hepatic lipid and glucose metabolism-related signaling pathways. Using the guinea pig maternal nutrient restriction (MNR) model of placental insufficiency and FGR, placenta efficiency and fetal weight were significantly improved following three administrations of a nonviral polymer-based nanoparticle gene therapy to the placenta from mid-pregnancy (<i>gestational day 35</i>) until <i>gestational day 52</i>. The nanoparticle gene therapy transiently increased expression of human insulin-like growth factor 1 (<i>hIGF1</i>) in placenta trophoblast. Fetal liver tissue was collected near-term at <i>gestational day 60</i>. Fetal sex-specific differences in liver gene and protein expression of profibrosis and glucose metabolism-related factors were demonstrated in sham-treated FGR fetuses but not observed in FGR fetuses who received placental <i>hIGF1</i> nanoparticle treatment. Increased plasma bilirubin, an indirect measure of hepatic activity, was also demonstrated with placental <i>hIGF1</i> nanoparticle treatment. We speculate that the changes in liver gene and protein expression and increased liver activity that result in similar expression profiles to appropriately growing control fetuses might confer protection against increased susceptibility to aberrant liver physiology in later life. Overall, this work opens avenues for future research assessing the translational prospect of mitigating FGR-induced metabolic derangements.<b>NEW & NOTEWORTHY</b> A placenta-specific nonviral polymer-based nanoparticle gene therapy that improves placenta nutrient transport and near-term fetal weight ameliorates growth restriction-associated changes to fetal liver activity, and cholesterol and glucose/nutrient homeostasis genes/proteins that might confer protection against increased susceptibility to aberrant liver physiology in later life. This knowledge may have implications toward removing predispositions that increase the risk of metabolic diseases, including diabetes, dyslipidemia, and nonalcoholic fatty liver disease in later life.