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

基本信息

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
项目类别：
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

项目摘要

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.

抽象的：宫内感染和绒毛膜羊膜炎是常见的妊娠并发症，与严重的妊娠相关。产妇、围产期和长期不良后果。不良产妇结局包括产后感染和败血症，而婴儿不良结局包括死产、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疗法来降低围产期死亡率和长期发病率绒毛膜羊膜炎相关性早产（ChorP）。引起绒毛膜羊膜炎的机制早产仍然知之甚少，但涉及绒毛膜羊膜炎引起的胎儿发育炎症反应综合征（FIRS）由全身炎症细胞因子增加定义浓度、脐带炎症和胎儿血管炎。 FIRS 导致心肺功能不良，新生儿的神经、视网膜和肾脏结局。鉴于超过 40 万例早产美国每年都会发生这种情况，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（ChorP）超出了目前抗生素治疗的范围。 Aqualung Therapeutics 有限公司确定了一种新的治疗 ChorP 靶点，即烟酰胺磷酸核糖转移酶 (NAMPT)，它是一种上游结合 Toll 样受体 4 (TLR4) 的高度炎症细胞酶，我们推测，有助于 FIRS 发展。我们最近证明，NAMPT 在患有以下疾病的女性胎盘中表达：绒毛膜羊膜炎的发病率显着增加，患有 ChorP 的女性体内 eNAMPT 水平升高等离子体。更重要的是，多克隆 eNAMPT 中和抗体 (pAb) 的 IV 递送 ChorP 的临床前怀孕小鼠模型，可减轻 FIRS、早产和支气管肺发育不良。我们推测 eNAMPT 对 ChorP 和 FIRS 做出了重大贡献发展。鉴于目前缺乏经批准的 ChorP 疗法，该 STTR 第一阶段的具体目标#1 该应用程序旨在验证 eNAMPT 作为 ChorP 生物标志物，并将高风险人群的血浆 eNAMPT 水平联系起来怀孕母亲（使用高度特异性的 ELISA 检测）患 ChorP 的风险。临床前 ChorP 研究中，具体目标 #2 将评估我们的领先 eNAMPT 中和人源化单克隆抗体 eNamptorTM 是否有效（目前正在稳定细胞系开发中）是一种针对妊娠小鼠的有效治疗干预措施利用野生型和 ChorP 改善 ChorP 死亡率和肺损伤（支气管肺发育不良） NAMPT-/- 杂合小鼠。这种学术与私人生物技术合作伙伴关系（亚利桑那大学水肺 Therapeutics）将利用大量的临床和转化专业知识来解决严重未满足的医疗问题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 ChorP 中以前未针对的途径。