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

摘要： 宫内感染和绒毛膜炎是常见的妊娠并发症， 孕产妇、围产期和长期不良结局。不利的产妇结局包括产后 感染和败血症，而不利的婴儿结果包括死产、早产、新生儿败血症、慢性 肺部疾病和脑损伤导致脑瘫和其他神经发育障碍。有一个 迫切需要找到新的疗法来降低围产期死亡率和长期发病率 绒毛膜炎相关早产（ChorP）。绒毛膜炎诱导的机制 早产仍然知之甚少，但涉及绒毛膜炎诱导的胎儿发育 炎症反应综合征（FIRS）定义为全身炎症细胞因子增加 浓度，脐带炎症和胎儿血管炎。FIRS导致心肺功能不佳， 新生儿的神经、视网膜和肾脏结果。鉴于超过40万的早产儿 在美国，每年都发生这种情况，但解决脉络膜炎相关并发症的需求尚未得到满足。 早产（ChorP）超出了目前的抗生素治疗。Aqualung Therapeutics，Corp. 确定了一种新的治疗ChorP的目标，烟酰胺磷酸核糖转移酶（NAMPT），上游 结合Toll样受体4（TLR 4）的高度炎性细胞酶，我们推测，它有助于FIRS 发展我们最近证实，NAMPT在患有子宫内膜异位症的妇女胎盘中的表达， ChorP女性患者的eNAMPT水平升高， 等离子体进一步至关重要的是，多克隆eNAMPT-中和抗体（pAb）在小鼠中的静脉内递送， ChorP的临床前妊娠小鼠模型，减弱了FIRS、早产的发展， 支气管肺发育不良我们推测eNAMPT对ChorP和FIRS有显著贡献 发展鉴于目前缺乏批准的ChorP疗法，本STTR I期的具体目标#1 该应用程序旨在验证eNAMPT作为ChorP生物标志物，并将血浆eNAMPT水平与高风险 孕妇（利用高度特异性ELISA测定）发展ChorP的风险。临床前ChorP 研究，具体目标#2将评估我们的领先eNAMPT中和人源化mAb，eNamptorTM （目前处于稳定的细胞系开发中）是一种有效的治疗干预妊娠鼠母鼠， 使用野生型和非野生型ChorP来改善ChorP死亡率和肺损伤（支气管肺发育不良） NAMPT-/-杂合子小鼠。这种学术-私人生物技术合作伙伴关系（亚利桑那大学-Aqualung 治疗学）将利用大量的临床和转化专业知识来解决严重的未满足的医疗需求。 需要通过改善新的信号传导来改善这种令人烦恼的疾病的早产发病率和死亡率 以前在ChorP中没有靶向的途径。

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.