Treatment of Preterm Birth with ProstaglandinF2alpha Receptor Modulators

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Preterm birth (PTB) is the leading cause of newborn death and the second leading cause of child death. Children born preterm often have lifelong health issues, including cerebral palsy, cognitive impairement, blindness, deafness, respiratory illness and gastrointestinal disorders, as well as chronic diseases such as hypertension and dyslipidemia. Hospital costs associated with PTB are among the most expensive: premature babies remain hospitalized an average of 11 days longer at a higher cost compared to term births; newborns born prior to 28 weeks gestation incur major costs (~$100,000/infant). In spite of a better understanding of risk factors and mechanisms related to premature contractions, and the introduction of public health prevention programs, the rate of PTB has increased. The economic implications of PTB make it the most costly medical urgency per patient. These statistics demonstrate that significant savings could be obtained by the development of effective treatments, which can prolong gestation, so called tocolytic agents. Prostaglandin-F2alpha (PGF2alpha) initiates labour, induces childbirth, and works in compliment with the small peptide hormone oxytocin, which is commonly used to induce labor in humans. Towards the development of a new tocolytic agent, we targeted the PGF2alpha receptor (FP) for two specific reasons: 1) FP expression increases during the initial phase of parturition, and 2) FP ''knock-out'' mice do not go into labour and must be delivered by cesarian. By creating a series of novel modulators, including peptide-based analogs proving successful in clinical studies, we have validated FP as a viable target. The proposed research is designed to further develop our prototypes to provide basic knowledge of the role of FP in parturition, to train highly qualified personnel in interdisciplinary research, and to develop effective therapy to treat preterm labour (PTL) to enhance quality of life from birth which impacts throughout life.