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A novel approach for prevention of Bronchopulmonary dysplasia in at-risk pre-term infants

预防高危早产儿支气管肺发育不良的新方法

基本信息

批准号：
10482142
负责人：
Suchismita Acharya
金额：
$ 110.91万
依托单位：
AYUVIS RESEARCH, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10482142
关键词：
Adolescent Adrenal Cortex Hormones Adult Affect Agreement Alveolar Angiogenic Factor Animals Anti-Inflammatory Agents Antiinflammatory Effect Bacteremia Binding Bolus Infusion Brain Bronchopulmonary Dysplasia Calcium Cardiac Cardiotoxicity Cell Death Cells Cessation of life Childhood Chitin Clinic Clinical Clinical Trials Complication Data Development Diagnosis Disease Dose Dysplasia Enzyme-Linked Immunosorbent Assay Exposure to Gases Genetic Predisposition to Disease Gestational Age Goals Gram-Negative Bacteria Gram-Negative Bacterial Infections Grant Growth Factor Human Hyperoxia Immune response Immunity Immunologist Impairment In Vitro Incidence Infant Infection Inflammation Inflammation Mediators Inflammatory Injections Interleukin-1 beta Interleukin-10 Interleukin-6 Intraperitoneal Injections Investigational New Drug Application Lead Life Lung Lymphocyte Measures Mechanical Ventilators Mechanical ventilation Modeling Molecular Weight Mus Neonatal No-Observed-Adverse-Effect Level Oligosaccharides Orphan Outcome Measure Oxygen Pathologic Pathway interactions Phagocytosis Pharmaceutical Preparations Phenotype Physiology Plasma Play Premature Birth Premature Infant Prevention Prevention approach Production Prophylactic treatment Proteins Protocols documentation Pulmonary Hypertension Pulmonary Inflammation Rattus Reactive Oxygen Species Recovery Regimen Reporting Research Respiratory Disease Respiratory Failure Rest Risk Role Safety Scientist Secondary to Series Serum Signal Transduction TLR4 gene TNF gene Techniques Testing Therapeutic Effect Time Toxicokinetics Transforming Growth Factor beta Treatment Efficacy Umbilical Cord Blood Universities Up-Regulation Utah Vascular Endothelial Growth Factors Vascularization Ventilator Work antagonist antenatal chronic respiratory disease comorbidity cytokine cytotoxicity drug development early childhood efficacy testing endothelial dysfunction experience genotoxicity human model improved in vitro testing intravenous injection lamb model lead candidate lung injury macrophage meetings monocyte mouse model neonatal mice neonate neurotensin mimic 1 novel novel strategies novel therapeutics peripheral blood prenatal preterm newborn prevent programs prophylactic pulmonary function pup respiratory response small molecule surfactant tissue repair vasculogenesis ventilation

项目摘要

ABSTRACT Bronchopulmonary Dysplasia (BPD) is the most common chronic respiratory disease in infants and is a devastating condition that disrupts the developmental program of the lung secondary to preterm birth. BPD affects neonates exposed to mechanical ventilation and, to date, there are no specific drugs available to prevent or treat this life-threatening condition. The pathologic hallmarks of BPD are hyperoxia-induced pulmonary inflammation, increased cell death, dysregulated angiogenic factors culminating in impaired alveolarization, dysregulated vascularization of the lung and pulmonary hypertension. AyuVis Research, Inc, is developing a novel class of low molecular weight natural oligosaccharide-derived small molecules which activate macrophage to a non-inflammatory phenotype via TLR4 signalling. In both mouse and preterm lamb BPD models, the lead candidate AVR-48 binds to TLR4 resulting in selective activation of the target cell to block inflammatory mediators in lung and upregulation of endogenous vascularization pathways improving lung vascularization/alveolization leading to improved lung function. Additionaly, it enhances production of certain host anti-inflammatory molecule such as IL-10 and growth factor VEGF with vascularization effects remaining local to lungs. AVR-48 also prevents the development of BPD associated pulmonary hypertension. We have demonstrated all these above mentioned therapeutic effects in two BPD models: intraperitoneal injection of AVR-48 prevents hyperoxia- induced BPD in a neonatal mice pup model at 10mg/kg dose and intravenous injection in invasive mechanical ventilator induced BPD in pre-term lambs at 3.0 mg/kg dose. In order to advance the lead candidate AVR-48, AyuVis is proposing three complimentary aims: (1) Determine safety and long-term efficacy in the preterm lamb model by testing whether prophylactic treatment with AVR-48 improves the long-term respiratory, cardiac and neurodevelopmental outcomes measured after 2 months of life to mimic 1-2 years of infant life; (2) Demonstrate anti-inflammatory effect of AVR-48 in human cord blood after LPS and hyperoxia challenges by measuring cytotoxicity, inflammatory and anti-inflammatory mediators and macrophage phenotypes (M1, M2, M1/M2); and (3) Determine toxicokinetic parameters in juvenile rats following GLP protocol that will be used to model human equivalent dose in clinic. These studies are expected to provide mechanistic and confirmatory efficacy data which would enable AVR-48 to progress to GMP manufacturing and file an Investigational New Drug application with the FDA.

摘要支气管肺发育不良(BPD)是婴儿最常见的慢性呼吸道疾病，是一种继发于早产的一种破坏肺部发育程序的破坏性状况。Bpd 影响暴露在机械通风下的新生儿，到目前为止，还没有特定的药物可用于预防或者治疗这种危及生命的疾病。BPD的病理特征是高氧性肺损伤。炎症，细胞死亡增加，调节失调的血管生成因子最终导致肺泡化受损，肺血管形成失调和肺高压。AyuVis研究公司正在开发一种新型低分子天然低聚糖小分子激活巨噬细胞通过TLR4信号转导到非炎症性表型。在小鼠和早产羔羊BPD模型中，铅候选AVR-48与TLR4结合导致靶细胞选择性激活以阻断炎症介质上调内源性血管生成途径促进肺血管化/肺泡化从而改善肺功能。此外，它还能增强某些宿主抗炎分子的产生。如IL-10和生长因子血管内皮生长因子，其血管形成作用仍局限于肺。AVR-48也预防BPD相关性肺动脉高压的发展。我们已经在上面演示了所有这些在两种BPD模型中提到的治疗效果：腹膜腔注射AVR-48预防高氧- 10 mg/kg剂量和机械侵袭下静脉注射诱导新生小鼠BPD 呼吸机3.0 mg/kg剂量诱导早产羔羊BPD。为了让领先的候选人AVR-48晋级， AyuVis提出了三个补充目标：(1)确定早产羔羊的安全性和长期疗效通过测试AVR-48预防性治疗是否改善长期呼吸、心脏和心脏功能在出生2个月后测量神经发育结果，以模拟婴儿1-2年的生活；(2)展示检测AVR-48对人脐血内毒素和高氧刺激后的抗炎作用细胞毒性、炎症和抗炎介质和巨噬细胞表型(M1、M2、M1/M2)；以及 (3)采用GLP方法测定幼年大鼠的毒代动力学参数，并将其用于人体模型临床当量剂量。这些研究有望提供机械性和验证性的疗效数据。这将使AVR-48能够进行GMP生产并提交调查性新药申请与食品药品管理局合作。