Abstract
Pregnancy complications adversely impact both mother and/or fetus throughout the lifespan. Fetal growth restriction (FGR) occurs when a fetus fails to reach their intrauterine potential for growth, it is the second highest leading cause of infant mortality, and leads to increased risk of developing non-communicable diseases in later life due 'fetal programming'. Abnormal placental development, growth and/or function underlies approximately 75% of FGR cases and there is currently no treatment save delivery, often prematurely. We previously demonstrated in a murine model of FGR that nanoparticle mediated, intra-placental human IGF-1 gene therapy maintains normal fetal growth. Multiple models of FGR currently exist reflecting the etiologies of human FGR and have been used by us and others to investigate the development of in utero therapeutics as discussed here. In addition to the in vivo models discussed herein, utilizing human models including in vitro (Choriocarcinoma cell lines and primary trophoblasts) and ex vivo (term villous fragments and placenta cotyledon perfusion) we have demonstrated robust nanoparticle uptake, transgene expression, nutrient transporter regulation without transfer to the fetus. For translational gene therapy application in the human placenta, there are multiple avenues that require investigation including syncytial uptake from the maternal circulation, transgene expression, functionality and longevity of treatment, impact of treatment on the mother and developing fetus. The potential impact of treating the placenta during gestation is high, wide-ranging across pregnancy complications, and may offer reduced risk of developing associated cardio-metabolic diseases in later life impacting at both an individual and societal level.