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

摘要： 宫内感染和绒毛膜羊膜炎是妊娠的常见并发症，与显著 母体、围产期和长期不良后果。不良的产妇结局包括产后 感染和败血症，而婴儿的不良结局包括死产、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 迫切需要找到新的治疗方法来降低围产期死亡率和糖尿病的长期发病率 绒毛膜羊膜炎相关性早产(CHIP)。绒毛膜羊膜炎的发病机制 早产仍然知之甚少，但涉及绒毛膜羊膜炎诱导的胎儿发育 全身炎性细胞因子升高定义的炎性反应综合征 浓度、脐带炎和胎儿脉管炎。冷杉会导致心肺功能不佳， 新生儿的神经学、视网膜和肾脏结局。考虑到超过40万早产儿 在美国，每年都会发生绒毛膜羊膜炎，但解决绒毛膜羊膜炎相关并发症的需求尚未得到满足 早产儿(CHAP)超出了目前抗生素治疗的范围。阿奎隆治疗公司已经 发现了一个新的治疗CHIP的靶点，烟酰胺磷酸核糖转移酶(NAMPT)，一种上游 与Toll样受体4(TLR4)结合的高度炎性细胞酶，我们推测，它与Firs有关 发展。我们最近已经证明，NAMPT在慢性阻塞性肺疾病患者胎盘中的表达 绒毛膜羊膜炎显著增加，患有慢性阻塞性肺疾病的妇女体内eNAMPT水平升高 血浆。更重要的是，静脉注射多克隆eNAMPT中和抗体(Pab)在 临床前妊娠小鼠模型的CHAP，减轻FIRS、早产和 支气管肺发育不良。我们推测eNAMPT对CHOP和FIRS有显著的贡献 发展。鉴于目前对慢性阻塞性肺疾病缺乏批准的治疗方法，这项STTR第一阶段的具体目标#1 应用程序旨在验证eNAMPT作为COMP生物标志物，并将高危人群的血浆eNAMPT水平联系起来 孕妇(利用高度特异性的酶联免疫吸附试验)对发生慢性阻塞性肺疾病的风险进行评估。处于临床前阶段 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发展中)是一种有效的治疗措施，用于治疗妊娠小鼠 利用野生型和获得性肺炎改善慢性支气管炎死亡率和肺损伤(支气管肺发育不良) NAMPT-/-杂合子小鼠。这种学术-私营生物技术合作伙伴关系(亚利桑那大学-阿夸隆 Treateutics)将利用大量的临床和翻译专业知识来解决严重的未满足的医疗问题 需要并通过改善新的信号来改善这种令人烦恼的疾病的早产发病率和死亡率 以前没有在Cchp中作为目标的路径。

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.