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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)

ABSTRACT: 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.

ORGANISM(S): Cavia porcellus

PROVIDER: GSE269097 | GEO | 2025/03/26

REPOSITORIES: GEO

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Project description:The etiology of fetal growth restriction (FGR) is multifactorial, although many cases often involve placental insufficiency. Placental insufficiency is associated with inadequate trophoblast invasion that results in an environment with high resistance to blood flow, decreased availability of nutrients to the placenta, and increased hypoxia. Despite accumulating knowledge linking inadequate trophoblast invasion with placental insufficiency and FGR, current treatment options are limited to iatrogenic delivery, usually preterm. We have developed a non-viral, polymer-based nanoparticle that facilitates transient human insulin-like 1 growth factor (hIGF1) gene delivery specifically to placental trophoblast. Using the established guinea pig maternal nutrient restriction (MNR) model of placental insufficiency and FGR, the aim of the study was to identify novel pathways in the sub-placenta/decidua that will provide insight into the underlying mechanism driving FGR, and may be corrected with hIGF1 nanoparticle treatment. Pregnant guinea pig dams underwent ultrasound-guided sham or hIGF1 nanoparticle treatment at mid-pregnancy, and sub-placenta/decidua tissue was collected 5 days later. Transcriptome analysis was performed using RNA Sequencing on the Illumina platform. Histological assessment of the sub-placenta/decidua demonstrated fewer maternal spiral arteries lined by trophoblast in the MNR sub-placenta/decidua which was associated with downregulation of genes involved in epithelium development and the regulation of cell migration. hIGF1 nanoparticle treatment results in marked changes to transporter activity in the MNR + hIGF1 sub-placenta/decidua when compared to sham MNR. Under normal growth conditions however, hIGF1 nanoparticle treatment in Control + hIGF1 sub-placenta/decidua was associated with downregulation of kinase signaling and increased proteolysis indicative of homeostasis. Overall, this study identified changes to the sub-placenta/decidua transcriptome that likely result in inadequate trophoblast invasion and that contribute to placental insufficiency. Additionally, this study has increased our understanding of pathways that hIGF1 nanoparticle treatment acts on in order to restore or maintain appropriate placenta function.

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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)

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