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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：
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.

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，由于早产而导致的破坏性的肺发育过程的疾病。BPD 影响暴露于机械通气的新生儿，迄今为止，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的病理特征是高氧诱导的肺动脉高压。炎症，增加的细胞死亡，失调的血管生成因子最终导致受损的肺泡化，肺血管形成失调和肺动脉高压。AyuVis Research，Inc正在开发一种活化巨噬细胞的新型低分子量天然寡糖衍生的小分子通过TLR 4信号传导转化为非炎症表型。在小鼠和早产羔羊BPD模型中，候选AVR-48与TLR 4结合，导致靶细胞的选择性活化以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，它还能促进某些宿主抗炎分子的产生如IL-10和生长因子VEGF，其血管形成作用保持在肺局部。AVR-48 预防BPD相关肺动脉高压的发展。我们已经证明了以上所有这些在两种BPD模型中提到的治疗效果：腹腔内注射AVR-48防止高氧- 在新生小鼠幼仔模型中以10 mg/kg剂量和在侵入性机械中静脉注射诱导BPD 在早产羔羊中，3.0 mg/kg剂量下呼吸机诱导的BPD。为了推进领先的候选人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有效性通过测试AVR-48预防性治疗是否改善了长期的呼吸、心脏和 2个月后测量的神经发育结果，以模拟1-2年的婴儿生活;（2）证明 AVR-48在人脐带血中在LPS和高氧激发后的抗炎作用，细胞毒性、炎症和抗炎介质和巨噬细胞表型（M1、M2、M1/M2）;和 (3)按照GLP方案确定幼龄大鼠的毒代动力学参数，该方案将用于人体建模临床等效剂量。预计这些研究将提供机制性和确证性疗效数据这将使AVR-48能够进展到GMP生产并提交研究性新药申请和食品药物管理局