Project Grant R01HD114495

DRUG REPURPOSING OF A NOVEL SYNTHETIC PROGESTIN FOR THE PREVENTION OF PRETERM LABOR AND FETAL INFLAMMATION - ABSTRACT INTRAUTERINE INFECTION/INFLAMMATION (IUI) IS A MAJOR CONTRIBUTOR TO PRETERM LABOR AND FETAL INFLAMMATION LEADING TO INJURY RESPONSES IN FETAL ORGANS SUCH AS THE BRAIN, LUNG AND THE GI TRACT. HOWEVER, THE MECHANISMS AND PRECISE THERAPEUTIC APPROACHES REMAIN ELUSIVE LARGELY BECAUSE OF LACK OF RELEVANT ANIMAL MODELS. WE HAVE DEVELOPED A POWERFUL NEW MODEL OF INTRAUTERINE INFECTION IN PRETERM RHESUS MACAQUES: INTRAAMNIOTIC (IA) INJECTION OF LIVE E. COLI FOLLOWED 24H LATER WITH ANTIBIOTICS. THIS MODEL RESULTS IN PERSISTENT IUI. IMPORTANTLY, THE MATERNAL AND FETAL INFLAMMATION PERSISTS DESPITE CLEARANCE OF E. COLI BACTEREMIA, RESULTING IN PRETERM LABOR (PTL), FETAL IMMUNE ABERRATIONS AND FETAL NEUROINFLAMMATION. AFTER AN EXPERT FDA PANEL RECOMMENDED WITHDRAWAL, THE ONLY DRUG APPROVED DRUG FOR PRETERM LABOR, 17-HYDROXY PROGESTERONE CAPROATE (17-HPC) WAS WITHDRAWN FROM THE MARKET BY ITS MANUFACTURER IN 2023. OUR DATA SUGGESTS THAT A MAJOR REASON FOR FAILURE OF 17-HPC IS THAT PROGESTERONE IS INACTIVATED INTRACELLULARLY BY AN ENZYME ENCODED BY THE GENE AKR1C1. WE FURTHER DEMONSTRATED THAT IUI INDUCES AKR1C1 EXPRESSION BOTH IN THE RHESUS MACAQUE UTERUS AND CHORIODECIDUA. WE THEREFORE PROPOSE USING A NOVEL SYNTHETIC PROGESTIN R5020 THAT IS RESISTANT TO AKR1C1 MEDIATED INACTIVATION. R5020 IS ALREADY IN CLINICAL USE IN SOME EUROPEAN COUNTRIES FOR MENOPAUSAL THERAPY AND CERTAIN GYNECOLOGICAL DISORDERS. THE GRANT IS BASED ON THE PREMISE THAT DRUG REPURPOSING OF A NOVEL PROGESTIN WITH FAVORABLE PHARMACOLOGICAL PROPERTIES OF ENHANCED AFFINITY FOR THE PROGESTERONE RECEPTOR AND RESISTANCE TO AKR1C1 INACTIVATION WILL BE AN EFFECTIVE THERAPEUTIC STRATEGY. WE PROPOSE TO TEST THE HYPOTHESIS THAT R5020 WILL REDUCE THE RESIDUAL MATERNAL AND FETAL INFLAMMATION IN INFECTIOUS MODELS THAT CLOSELY SIMULATE IUI IN PREGNANT WOMEN WITH TWO AIMS. IN AIM 1, WE WILL TEST IF R5020 WILL DECREASE IUI INDUCED INFLAMMATION AND PRETERM LABOR. WE WILL USE STATE-OF-THE-ART SINGLE-NUCLEUS TRANSCRIPTOMIC APPROACH AND INFLAMMATORY MARKER DISCOVERY SCIENCE TO UNRAVEL CELLULAR AND MOLECULAR MECHANISMS OF INFLAMMATION AT THE MATERNAL-FETAL INTERFACE, AND DEFINE LABOR ASSOCIATED PATHWAYS OF IUI. USING MULTI-PARAMETER FLOW CYTOMETRY, WE WILL IDENTIFY MECHANISMS OF NEUTROPHIL RECRUITMENT AND ACTIVATION IN THE CHORIO-DECIDUA. IN AIM 2, WE WILL IDENTIFY SYSTEMIC FETAL IMMUNE PERTURBATIONS RESULTING FROM IUI. WE WILL DETERMINE IF R5020 CAN REDUCE FETAL SYSTEMIC INFLAMMATION. WE WILL UNCOVER MECHANISMS OF NEUROINFLAMMATION RESULTING FROM IUI BY SINGLE NUCLEUS RNA SEQ AND MULTI-PARAMETER IMMUNOHISTOLOGY. THESE STUDIES WILL DEVELOP THE CRITICAL KNOWLEDGE BASE FOR FUTURE STUDIES AIMED AT REPURPOSING OF R5020 AS A NOVEL PRETERM LABOR PREVENTATIVE THERAPY FOR HUMAN IUI. A COLLABORATIVE MULTI-DISCIPLINARY TEAM WILL USE HIGH-RESOLUTION IMMUNOLOGY, GENOMICS/PROTEOMICS, NEURO-SCIENCE, AND TRANSLATIONAL APPROACHES IN MODELING IUI AND FETAL INFLAMMATION IN AN ANIMAL MODEL THAT CLOSELY MIMICS THE HUMAN PATHOLOGY.