Project Summary Improved methods for assessing pregnancy well-being, and assessing possible molecular and genetic correlates of poor pregnancy outcomes are currently in development. This knowledge is of limited value, however, without the ability to intervene in troubled pregnancies. The obvious difficult step is to translate knowledge to be gained into placental therapeutics to improve fetal health. Treating the placenta within the pregnant mother has several significant concerns. Placental therapeutics will need to selectively target the placenta to avoid unwanted off-target effects on maternal physiology and to ensure that treating the placenta does not result in inadvertent negative consequences for the fetus. The long-term goal is to establish safe, efficacious and placenta-specific gene therapy in a nonhuman primate in order to establish potential treatment strategies for fetal growth restriction and other pregnancy pathologies in which the placenta plays a role. Furthermore, the development of an organ-specific targeting approach in a nonhuman primate will allow the development of other disease-specific models of pregnancy in an animal model highly translatable to human. The overall objective of this application is to assess the feasibility and safety of a polymer-based nanoparticle that can be taken up by the placental syncytium and result in transgene expression and allow tracking and targeting developments for organ-specific delivery of nanocarriers. The rationale behind this proposal is that it is expected to make significant steps toward a specific, translatable delivery mechanism for therapy in the placenta and to broaden the capabilities of disease modelling in the nonhuman primate. These forward-looking and innovative studies will position University of Florida and University of Wisconsin- Madison investigators to be poised to work towards the ultimate goal, to be able to “treat the placenta”, an ephemeral organ fundamental to our existence, yet exceedingly difficult to address with therapeutic intervention, in the interest of improving pregnancy outcomes, women’s health and lifelong health. This study will also open possibilities for other organ-specific disease models to be developed in the nonhuman primate.