Extracellular NAMPT is a Novel Therapeutic Target in Chorioamnionitis-Related Prematurity (ChorP)

Information

  • Research Project
  • 10081144
  • ApplicationId
    10081144
  • Core Project Number
    R41HD101202
  • Full Project Number
    1R41HD101202-01A1
  • Serial Number
    101202
  • FOA Number
    PA-19-270
  • Sub Project Id
  • Project Start Date
    9/18/2020 - 4 years ago
  • Project End Date
    8/31/2021 - 3 years ago
  • Program Officer Name
    GIACOIA, GEORGE
  • Budget Start Date
    9/18/2020 - 4 years ago
  • Budget End Date
    8/31/2021 - 3 years ago
  • Fiscal Year
    2020
  • Support Year
    01
  • Suffix
    A1
  • Award Notice Date
    9/18/2020 - 4 years ago

Extracellular NAMPT is a Novel Therapeutic Target in Chorioamnionitis-Related Prematurity (ChorP)

ABSTRACT: Intrauterine infection and chorioamnionitis are common complications of pregnancy associated with significant maternal, perinatal, and long-term adverse outcomes. Adverse maternal outcomes include postpartum infections and sepsis while adverse infant outcomes include stillbirth, premature birth, neonatal sepsis, chronic lung disease and brain injury leading to cerebral palsy and other neurodevelopmental disabilities. There is a desperate need to identify novel therapies to reduce the perinatal mortality and long-term morbidity of chorioamnionitis-related prematurity (ChorP). The mechanisms responsible for chorioamnionitis-induced preterm birth remain poorly understood but involve chorioamnionitis-induced development of the fetal inflammatory response syndrome (FIRS) defined by increased systemic inflammatory cytokine concentrations, inflammation of the umbilical cord, and fetal vasculitis. FIRS leads to poor cardiorespiratory, neurological, retinal, and renal outcomes in the newborn infants. Given that over 400,000 premature births occur each year in the US, there is an unmet need to address the complications of chorioamnionitis-related prematurity (ChorP) beyond the current therapy of antibiotic administration. Aqualung Therapeutics, Corp. has identified a novel therapeutic ChorP target, nicotinamide phosphoribosyltransferase (NAMPT), an upstream highly inflammatory cytozyme that binds Toll-like receptor 4 (TLR4) and, we speculate, contributes to FIRS development. We have recently demonstrated that NAMPT expression in placentas from women with chorioamnionitis is dramatically increased and that women with ChorP have elevated eNAMPT levels in their plasma. Of further critical importance, the IV delivery of a polyclonal eNAMPT-neutralizing antibody (pAb) in the preclinical pregnant mouse model of ChorP, attenuates the development of FIRS, premature delivery, and bronchopulmonary dysplasia. We speculate eNAMPT to significantly contribute to ChorP and FIRS development. Given the lack of currently approved therapies for ChorP, Specific Aim #1 of this STTR Phase I application is designed to validate eNAMPT as a ChorP biomarker and link plasma eNAMPT levels in high risk pregnant mothers (utilizing a highly specific ELISA assay) to the risk of developing ChorP. In preclinical ChorP studies, Specific Aim #2 will assess whether our lead eNAMPT-neutralizing humanized mAb, eNamptorTM (currently in stable cell line development) is an effective therapeutic intervention for pregnant murine dams with ChorP to ameliorate ChorP mortality and lung injury (bronchopulmonary dysplasia) utilizing wild type and NAMPT-/- heterozygous mice. This academic-private biotech partnership (University of Arizona-Aqualung Therapeutics) will leverage substantial clinical and translational expertise to address a serious unmet medical need and improve preterm morbidity and mortality in this vexing disorder by ameliorating novel signaling pathways not previously targeted in ChorP.

IC Name
EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT
  • Activity
    R41
  • Administering IC
    HD
  • Application Type
    1
  • Direct Cost Amount
  • Indirect Cost Amount
  • Total Cost
    265096
  • Sub Project Total Cost
  • ARRA Funded
    False
  • CFDA Code
    865
  • Ed Inst. Type
  • Funding ICs
    NICHD:265096\
  • Funding Mechanism
    SBIR-STTR RPGs
  • Study Section
    ZRG1
  • Study Section Name
    Special Emphasis Panel
  • Organization Name
    AQUALUNG THERAPEUTICS CORP.
  • Organization Department
  • Organization DUNS
    097938637
  • Organization City
    TUCSON
  • Organization State
    AZ
  • Organization Country
    UNITED STATES
  • Organization Zip Code
    857186617
  • Organization District
    UNITED STATES