Placental-specific therapy for fetal growth restriction

Project Summary: Our goal in this competitive renewal of our current award is to develop a therapy that targets the placenta directly, will be effective in later pregnancy following diagnosis of Fetal Growth Restriction (FGR) and investigate treatment impact on the fetal, and offspring brain and heart. Development of non-viral, biodegradable, targeted therapeutics for placental insufficiency could significantly impact infant morbidity and mortality and reduce the risk of fetal programming leading to metabolic disorder and cardiovascular problems in later life. Polymeric nanoparticles have passed safety regulations and are already being used in human clinical studies as treatments for cancers. We utilize a biosynthetic co-polymer, complexed with a plasmid containing the Insulin-like Growth Factor 1 (IGF-1) gene under the control of trophoblast specific promotors and have successfully shown efficient nanoparticle uptake into human syncytiotrophoblast ex and in vivo using animal models of FGR (surgically- induced, genetic manipulation, nutrient restricted). In utero placental therapy challenges current paradigms for the management of FGR and potentially other pregnancy complications which may benefit from improvement of the in utero environment, such as preterm birth with sterile inflammation. In addition, our studies will provide more insight into the mechanisms of fetal programming of the brain and cardiovascular system and the impact of specific, placenta-only intervention of ameliorating the long-term impacts of being born to small. The use of placentally-targeted therapeutics is highly innovative, challenging current paradigms for the management of fetal growth restriction and moving gene therapy beyond imaging, targeting, and destruction of unwanted cells. The proposed research is significant because development of a placental therapeutic allows manipulation of the in utero environment and ultimately such capabilities and knowledge has the potential to lead to the development of the first effective treatment for Fetal Growth Restriction. This application is directly responsive to two of the topics of special emphasis in the recently re-issued "Notice of Special Interest (NOSI): High Priority Areas in Placental Research for Healthy Pregnancies" (Reissue) NOT-HD-22-049 including elucidation of the molecular mechanisms (e.g., transcriptional regulatory pathways and system biology approaches), involved in the pathophysiology of placental disorders, and development of targeted therapeutic strategies to prevent and treat pregnancy complications and/or fetal conditions.