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

细胞外 NAMPT 是绒毛膜羊膜炎相关早产儿 (ChorP) 的新型治疗靶点

• 批准号: 10081144
• 负责人: Mohamed Ahmed
• 金额: $ 26.51万
• 依托单位: AQUALUNG THERAPEUTICS CORP.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-18 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10081144
• 关键词: ADME Study; Acute; Address; Adult Respiratory Distress Syndrome; Affinity; Animal Model; Antibiotic Therapy; Antibiotics; Arizona; Attenuated; Binding; Biological; Biological Assay; Biological Markers; Biological Response Modifier Therapy; Biotechnology; Brain Injuries; Bronchopulmonary Dysplasia; Cell Line; Cerebral Palsy; Chinese Hamster Ovary Cell; Chronic; Chronic lung disease; Clinical; Clinical Trials; Clone Cells; Collaborations; Data; Development; Disease; Enzyme-Linked Immunosorbent Assay; Fetal Development; Functional disorder; Genetic Transcription; Goals; Hand; Human; Individual; Infant; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Investigational Drugs; Kidney; Lead; Ligands; Link; Liquid substance; Mammalian Cell; Medical; Morbidity - disease rate; Mothers; Mus; Natural Immunity; Neurodevelopmental Disability; Neurologic; Newborn Infant; Outcome; Pancreatitis; Perinatal; Perinatal mortality demographics; Phase; Placenta; Plasma; Postpartum Period; Pregnancy Complications; Pregnant Women; Premature Birth; Premature Infant; Premature Mortality; Privatization; Publishing; Pulmonary Fibrosis; Pulmonary Hypertension; Radiation; Reagent; Retina; Risk; Scientist; Sepsis; Severities; Signal Pathway; Small Business Technology Transfer Research; TLR4 gene; Therapeutic; Therapeutic Intervention; Therapeutic Monoclonal Antibodies; Tissues; Treatment Efficacy; Umbilical cord structure; Universities; Validation; Vasculitis; Woman; Work; adverse maternal outcomes; adverse outcome; cytokine; design; extracellular; fetal; fetal inflammatory response syndrome; high risk; humanized monoclonal antibodies; improved; infant morbidity/mortality; infant outcome; intraamniotic infection; intrauterine infection; lung injury; mortality; mouse model; neonatal sepsis; neutralizing antibody; new therapeutic target; nicotinamide phosphoribosyltransferase; novel; novel marker; novel therapeutics; pre-clinical; preclinical study; pregnant; premature; premature lungs; public health relevance; pulmonary arterial hypertension; safety study; stable cell line; stillbirth; therapeutic target; tissue biomarkers

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.

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