Placental Nanoparticle-mediated IGF1 Gene Therapy Corrects Fetal Growth Restriction in a Guinea Pig Model

Abstract

ABSTRACTFetal growth restriction (FGR) caused by placental insufficiency is a major contributor to neonatal morbidity and mortality. There is currently no in utero treatment for placental insufficiency or FGR. The placenta serves as the vital communication, supply, exchange, and defense organ for the developing fetus and offers an excellent opportunity for therapeutic interventions. Here we show efficacy of repeated treatments of trophoblast-specific humaninsulin-like 1 growth factor(IGF1) gene therapy delivered in a non-viral, polymer nanoparticle to the placenta for the treatment of FGR. Using the guinea pig maternal nutrient restriction model of FGR, nanoparticle-mediatedIGF1treatment was delivered to the placenta via ultrasound guidance across the second half of pregnancy, after establishment of FGR. This treatment resulted in correction of fetal weight in MNR animals compared to control, improved fetal physiology and no negative maternal side-effects. Overall, we show for the first time a therapy capable of improving the entire pregnancy environment: maternal, placental, and fetal. This combined with our previous studies using this therapy at both mid pregnancy and in numerous cell and animal models demonstrate the plausibility of this therapy for future human translation to improve health outcomes of neonates and decrease numerous morbidities associated with the developmental origins of disease.