In the United States, one in ten babies is born prematurely. The earlier in pregnancy a baby is born, the morelikely they will have an extended hospital stay, as well as serious health complications such as respiratorydistress syndrome, necrotizing enterocolitis, deafness, vision problems and cerebral palsy. Maternal stress is awell-established risk factor for preterm birth, and recent studies using a mouse model of maternal stress highlightthe role of a stress response protein, FKBP51, in promoting preterm birth. Prior work demonstrates that stressboosts FKBP51 expression. Consequently, FKBP51 binds to progesterone receptors in decidual cells at thematernal-fetal interface, reducing progesterone receptor activity in the nucleus, resulting in the functionalwithdrawal of progesterone that triggers labor and birth in humans. Importantly, this novel molecular pathwaycan be blocked by 15-deoxy-Î12,14-prostaglandin J2 (15dPGJ2), restoring the activity of progesterone receptorsin vitro and in vivo. Thus, therapeutic targeting of FKBP51 has great potential as a safe and effective strategy toprevent preterm birth. Because there exist no pharmacological strategies for the prevention of preterm birth,Daré Bioscience, in collaboration with the University of South Florida, aims to rigorously demonstrate thefeasibility of targeting FKBP51 to improve obstetric treatment options for women. Work in Aim 1 is focused onvalidating FKBP51 as a novel drug target using clinically-relevant human decidual cell culture models, selectinga therapeutic strategy that combines 15dPGJ2 with delivery of a progestin, and evaluating the downstreambiological effects of treatment. The focus of Aim 2 is to demonstrate the in vivo safety and efficacy of 15dPGJ2plus progestin combination therapy for pregnancy maintenance in a previously validated maternal stress inducedmouse model of preterm birth. The goal is to demonstrate a statistically significant increase in gestational lengthby treatment(s) in stressed animals vs. untreated stressed controls. This project has significant translational andcommercial potential because it will provide the necessary proof-of-concept data to advance a treatment strategyto Phase II IND-enabling studies.
Public Health Relevance Statement: Infants that are born prematurely, before 37 weeks of pregnancy, are likely to have more health problems than
those carried to term, including serious health problems that affect the brain, lungs, vision, and hearing. There
are no FDA-approved strategies to prevent and/or suppress preterm birth. Strategies to target FKBP51 and
stress-induced preterm birth have high potential to change the standard of care for at-risk mothers and
significantly improving outcomes for infants.
Project Terms: | <0-4 weeks old> | | | | | | 