Identification of modifications to the maternal-fetal interface transcriptome associated with placental insufficiency and a novel gene therapy for the treatment of fetal growth restriction (Placenta)

Fetal growth restriction (FGR) affects between 5-10% of all live births. Placental insufficiency is a leading cause of FGR, resulting in reduced nutrient and oxygen delivery to the fetus. Currently, there is no effective in utero treatment options for FGR, or placental insufficiency. We have developed a gene therapy to deliver human insulin-like 1 growth factor (hIGF1) to the placenta via a non-viral nanoparticle delivery mechanism as potential treatment of FGR. Using a guinea pig maternal nutrient restriction (MNR) model of FGR, we aimed to understand the transcriptional changes within the placenta associated with placental insufficiency that occur at the beginning stages of FGR (mid-pregnancy), and the immediate impact of hIGF1 nanoparticle treatment on the placental transcriptome. Using RNAsequencing, we analyzed protein coding genes of three experimental groups: Control dams and MNR receiving a sham treatment, and MNR dams receiving hIGF1 nanoparticle treatment. Pathway enrichment analysis comparing MNR placentas to Control revealed upregulation of pathways associated with degradation and repair of genetic information and downregulation of pathways associated with transmembrane transport. Similarly, differentially expressed genes that were decreased in MNR + hIGF1 placentas compared to Control demonstrated downregulation in pathways relating to transporter activities, but upregulation in pathways associated with positive regulation of phosphorylation and kinase activity. When compared to MNR placentas, MNR + hIGF1 placentas demonstrated changes to genes associated with transmembrane transporter activity including ion, vitamin and solute carrier (SLC-mediated) transport. Overall, this study identifies the key signaling and metabolic changes occurring in the placenta that contribute to placental insufficiency, and increases our understanding of the pathways that increasing placental IGF1 expression acts on and corrects. Female (dams) Dunkin-Hartley guinea pigs were assigned to either the control diet group (n = 4) or MNR diet group (n = 7). Control dams were provided food and water was ad libitum; MNR dams were provided water ad libitum however, food intake was restricted to 70% per kilogram body weight of the Control group. At GD30-33, dams underwent an ultrasound-guided, transuterine, intra-placental injection of either sham (Control and MNR) or hIGF1 nanoparticle (MNR). Dams were sacrificed five (GD35-38) days after hIGF1 nanoparticle treatment. Placenta tissue from two fetuses per litter (one female and one male) was blunt dissected away from the rest of the maternal-fetal interface and snap-frozen in liquid nitrogen for RNA extraction. RNA-Seq Libraries for each gender and experimental group were generated using the Illumina Stranded mRNA Prep Kit. RNA-Seq Libraries were sequenced using the Illumina NovaSeq platform.