PROJECT SUMMARY
Preterm birth (PTB), or birth before 37 weeks of gestation, was the second leading cause of infant death in the
US in 2017. Each year, more than $26 billion is spent on treatment and care of babies born prematurely, not
accounting for the lifelong impact of developmental and cognitive impairments. Earlier this year, the FDA
issued a recommendation that the synthetic progestin 17-hydroxyprogesterone caproate (OHPC, Makena®),
the only approved product for PTB prevention, be withdrawn from the market due to lack of clinical benefit in a
required post-market study. New and innovative therapeutic options for preventing PTB are desperately
needed, but the etiology of PTB is complex and the potential for tissue sampling and clinical trials during
pregnancy is limited. We recently developed an adapted mouse model of inflammation-induced PTB and a
unique nanomedicine-based approach for more efficient vaginal delivery of therapeutics to the reproductive
tract. Together, these new tools led to the first demonstration of therapeutic prevention of early intrauterine
inflammation-induced PTB that led to full term delivery of litters with high percentages of pup viability and
neurotypical motor development. The therapeutics delivered via the nanoformulation were histone deacetylase
inhibitors (HDACi) dosed with or without the need for additional exogenous progesterone (P4). HDACi prevent
deacetylation of histones, leading to more transcriptionally active chromatin, and thus, changes in gene
expression. We also observed that the P4/HDACi combination inhibited human myometrial cell contractility and
led to an increase in the ratio of P4 receptor (PR) isoform B (PR-B) compared to P4 receptor isoform A (PR-A),
which is thought to maintain uterine quiescence and cervical competence. This supports the idea that HDACi-
induced hyperacetylation creates a more favorable chromatin structure for ligand-bound PR to change the
gene expression profile in a manner that prevents PTB. The overarching goals of this proposal are to
determine the role of PR-B in the prevention of inflammation-induced PTB, to map epigenetic changes that are
specific to therapeutic treatment, and to evaluate whether the epigenetic changes are sufficient to reset the
uterine environment for normal fetal development. If these preclinical studies are successful, we will generate
fundamental mechanistic knowledge of epigenetic regulation in PTB, as well as identify new cellular pathways
that may be important targets for PTB prevention.
