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：
10616606
负责人：
Suchismita Acharya
金额：
$ 70.21万
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/10616606
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 Endothelial Growth Factors Enzyme-Linked Immunosorbent Assay Exposure to Gases Genetic Predisposition to Disease Gestational Age Goals Gram-Negative Bacteria Gram-Negative Bacterial Infections Grant 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 Macrophage 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 Uterus 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 immunoregulation improved in vitro testing intravenous injection lamb model lead candidate lung injury manufacture meetings monocyte mouse model neonatal mice neonate neurotensin mimic 1 novel novel strategies novel therapeutics peripheral blood pre-Investigational New Drug meeting 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.

抽象的支气管肺发育不良（BPD）是婴儿最常见的慢性呼吸道疾病，是一种继发于早产的破坏性病症，会破坏肺部的发育程序。边缘性PD 影响接受机械通气的新生儿，迄今为止，尚无特效药物可预防或治疗这种危及生命的疾病。 BPD 的病理特征是高氧诱导的肺损伤炎症、细胞死亡增加、血管生成因子失调，最终导致肺泡化受损，肺血管化失调和肺动脉高压。 AyuVis Research, Inc 正在开发一种新型低分子量天然寡糖衍生小分子，可激活巨噬细胞通过 TLR4 信号转变成非炎症表型。在小鼠和早产羔羊 BPD 模型中，候选 AVR-48 与 TLR4 结合，导致靶细胞选择性激活，从而阻断炎症介质在肺中和内源性血管化途径的上调改善肺血管化/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例如 IL-10 和生长因子 VEGF，其血管化作用仍保留在肺部局部。还有AVR-48 预防 BPD 相关肺动脉高压的发展。上面我们已经演示了所有这些提到在两个 BPD 模型中的治疗效果：腹腔注射 AVR-48 可预防高氧血症在新生小鼠幼鼠模型中以 10mg/kg 剂量和侵入性机械静脉注射诱导 BPD 呼吸机在 3.0 mg/kg 剂量下诱导早产羔羊 BPD。为了推进主要候选药物 AVR-48， 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 2 个月后测量神经发育结果，模拟 1-2 岁的婴儿生活； (2) 演示通过测量 LPS 和高氧挑战后 AVR-48 在人脐带血中的抗炎作用细胞毒性、炎症和抗炎介质以及巨噬细胞表型（M1、M2、M1/M2）；和 (3) 按照 GLP 方案确定幼年大鼠的毒代动力学参数，用于模拟人类相当于临床剂量。这些研究预计将提供机制和验证性疗效数据这将使 AVR-48 能够进入 GMP 生产阶段并提交新药研究申请与 FDA 合作。