Project Grant R44HD113465

THERAPEUTIC TARGETING OF FKBP51 FOR THE PREVENTION OF STRESS-INDUCED PRETERM BIRTH - SUMMARY IN THE UNITED STATES, ONE IN TEN BABIES IS BORN PREMATURELY, OFTEN LEADING TO EXTENDED HOSPITAL STAYS AND SERIOUS HEALTH ISSUES SUCH AS RESPIRATORY DISTRESS SYNDROME, NECROTIZING ENTEROCOLITIS, DEAFNESS, VISION PROBLEMS, AND CEREBRAL PALSY. MATERNAL AND FETAL STRESS ARE KNOWN RISK FACTORS FOR PRETERM BIRTH, WITH RECENT MOUSE MODEL STUDIES HIGHLIGHTING THE ROLE OF THE STRESS RESPONSE PROTEIN FKBP51 IN THIS PROCESS. STRESS INCREASES LEVELS OF FKBP51, WHICH THEN BINDS TO PROGESTERONE RECEPTORS IN DECIDUAL CELLS, INHIBITING THEIR ACTIVITY, THEREBY TRIGGERING THE FUNCTIONAL WITHDRAWAL OF PROGESTERONE THAT LEADS TO PRETERM LABOR. THIS PATHWAY CAN BE BLOCKED BY 15-DEOXY- D12,14-PROSTAGLANDIN J2 (15DPGJ2), WHICH RESTORES PROGESTERONE RECEPTOR ACTIVITY BY REDUCING STRESS-INDUCED FKBP51 LEVELS AND FKBP51-PR INTERACTION. TARGETING FKBP51 OFFERS A PROMISING STRATEGY FOR PREVENTING PRETERM BIRTH, AN AREA WITH NO EXISTING PHARMACOLOGICAL OPTIONS. IN SUCCESSFUL PHASE I STUDIES, DARE BIOSCIENCE, IN COLLABORATION WITH THE UNIVERSITY OF SOUTH FLORIDA, VALIDATED UTERINE FKBP51 AS A DRUG TARGET FOR THE PREVENTION OF STRESS INDUCED PRETERM BIRTH AND FURTHER DEMONSTRATED THE FEASIBILITY OF BLOCKING FKBP51 WITH 15DPGJ2 USING HUMAN CELLS AND MOUSE MODELS. PHASE II WORK AIMS TO FORMULATE 15DPGJ2 WITH PROGESTERONE AS A MINI-TABLET VAGINAL INSERT AND OPTIMIZE THE TREATMENT REGIMEN IN THE MOUSE. THE OPTIMIZED TREATMENT WILL THEN BE EVALUATED IN STANDARD PRECLINICAL STUDIES FOCUSING ON PHARMACOKINETICS, SAFETY, AND TOXICITY. DATA COLLECTED DURING PHASE II WILL FACILITATE A SUCCESSFUL PRE-IND MEETING WITH THE FDA. OUR GOAL IS TO DEVELOP A SAFE AND EFFECTIVE THERAPY TO PREVENT PRETERM BIRTH, WITH BROAD IMPLICATIONS FOR IMPROVING NEONATAL AND MATERNAL HEALTH OUTCOMES.