Placental nanoparticle-mediated IGF1 gene therapy corrects fetal growth restriction in a guinea pig model.

Abstract

Fetal 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 human insulin-like 1 growth factor (IGF1) gene therapy delivered in a non-viral, polymer nanoparticle to the placenta for the treatment of FGR. Using a guinea pig maternal nutrient restriction model (70% food intake) of FGR, nanoparticle-mediated IGF1 treatment 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 + IGF1 animals compared to sham treated controls on an ad libitum diet, increased fetal blood glucose and decreased fetal blood cortisol levels compared to sham treated MNR, and showed no negative maternal side-effects. Overall, we show a therapy capable of positively impacting the entire pregnancy environment: maternal, placental, and fetal. This combined with our previous studies using this therapy at mid pregnancy in the guinea pig and in two different mouse model and three different human in vitro/ex vivo models, demonstrate the plausibility of this therapy for future human translation. Our overall goal is to improve health outcomes of neonates and decrease numerous morbidities associated with the developmental origins of disease.