PROJECT SUMMARY/ABSTRACT Particle-based fetal therapy is a promising approach to address organ damage caused by structural diseases in utero. By prenatal imaging, structural diseases can be diagnosed and imaging features can predict the severity of outcome. Fetal surgery has demonstrated improved outcomes (but not cures) for structural diseases such as congenital diaphragmatic hernia (CDH), where lung growth is impaired and spina bifida (MMC) where the unprotected spinal cord is damaged. The challenges with fetal surgery are the complexity and invasive nature of these procedures and the limit to how early in pregnancy these techniques can be applied. In most cases, earlier treatment results in shortened duration of organ damage and longer duration of normal organ growth and development. We have generated data that nanoparticles (NPs) carrying epigenetic therapy in the form of specific microRNAs changes various downstream targets and improves the growth of lung in a rat of CDH. This approach can be delivered safely through a needle very early in pregnancy by clinical techniques that carry a very low rate of fetal demise (amniocentesis and fetal blood transfusion). To improve on our success in these animal models, we will engineer particles for two modes of delivery: 1) systemic/intravenous (IV) to reach internal organs (lung) and 2) intra-amniotic (IA) to reach tissues sites that are in contact with the amniotic fluid (such as the lung epithelial surface). In aim 1, we will test and improve particle behavior (stability and controlled protein binding) in human fetal blood to improve IV delivery. We will then use optimized particles to deliver epigenetic therapy to improve lung morphology in the rat model of CDH. In aim 2, we will test and improve particle behavior and stability in rat, lamb and human amniotic fluid to improve IA delivery. We will use particles carrying epigenetic therapy to treat a rat model CDH. Finally, with an eye on translation, in aim 3, we will test the distribution of particles in lamb after IV or IA administration to lung and other tissues. This project takes advantage of the synergistic expertise (biomedical engineering and fetal therapy) of the two principal investigators who have already worked together for several years. Successful completion of our aims will establish principles with broad implications for fetal therapy, would inform strategies to improve outcomes for children afflicted with congenital diseases. Our strategies—which aim for clinical translation—could lead to a paradigm-changing “off-the-shelf” therapy for structural diseases that, due to their simplicity, could be offered at many hospitals.

PROJECT NARRATIVE Structural diseases diagnosed before birth, such as diaphragmatic hernia, cause significant morbidity in children due to tissue damage and inadequate organ development. Fetal therapy, to allow more normal organ development, through invasive procedures has demonstrated some benefit but more minimally invasive procedures are needed to allow for treatment earlier in pregnancy to further improve organ development. Synthetic nanoparticles, made from biocompatible polymers, serve as a platform to treat structural fetal diseases in a minimally invasive fashion and we will study these particles with the intent to treat fetal lung disease.