Development of Non-invasive Liquid Biopsy Screening Tool for Preterm Birth Causes and Consequences

Program Director/Principal Investigator (Last, First, Middle): Peters, David, G. Abstract The overarching goal of this study is to develop epigenomic liquid biopsy methods for both the early detection and ongoing prediction of the clinical trajectories that result in preterm birth (PTB). PTB is the most important problem in modern obstetrics. Despite ongoing efforts to understand its etiologies, there are no screens that reliably identify at-risk expectant mothers early in gestation. Furthermore, in the case of preeclampsia (PE), the clinical trajectory of disease, once diagnosed, is difficult to predict. Similarly, for fetuses affected by intrauterine growth restriction (IUGR) it is impossible to identify in early gestation those that will have the poorest outcomes. Building on our pioneering work in non-invasive prenatal testing (NIPT) we propose to develop a liquid biopsy screen for PTB and analytical methods that will predict the clinical trajectories of PE and IUGR. Liquid biopsy of cell-free DNA (cfDNA) is a powerful tool for non-invasive diagnosis and phenotyping of human disease. cfDNA contains a wealth of biologically important information, if one has the analytical tools to exploit it. For example, methylation signatures on cfDNA fragments in maternal plasma contain information relating to their tissue(s) of origin, as well as indicators of epigenomic dysregulation associated with pathological changes within those tissues. We have developed analytical methods that can detect DNA methylation changes in maternal and fetal tissues many weeks before the onset of PTB. The cascade of events that culminate in PTB has several possible underlying pathophysiological pathways. These pathways may be initiated weeks to months before clinically apparent preterm labor or preterm rupture of membranes. We propose to develop two kinds of "early warnings". One will predict the trajectories of pregnancies, particularly pregnancies that experience mild or severe preeclampsia (PE) (Aim 1) or IUGR (Aim 2). These predictions will be made after a clinical diagnosis and are intended to help with clinical management of the pregnancy. The other will be a screen, administered between weeks 10 and 13, for pregnancies that are likely to end in preterm birth (Aim 3).