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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：
10765750
负责人：
Suchismita Acharya
金额：
$ 20.4万
依托单位：
AYUVIS RESEARCH, INC.
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10765750
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 Canis familiaris 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 Glucosamine 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 Injury 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 Neonatal Intensive Care Units Newborn Infant 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 Pulmonary Hypertension Pulmonary Inflammation Rattus Recovery Regimen Reporting Research Respiratory Disease Respiratory Failure Rest Risk Role Safety Scientist Secondary to Series Serine Serum Signal Transduction TLR4 gene TNF gene Techniques Testing Threonine 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 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 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. Our 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 leading to improved lung function. AVR-48 has a glucosamine core, making it responsive to O-GlcNAcylation of serine/threonine of lung proteins, a conserved defense against injury that enables cellular remodeling. 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. We have demonstrated that 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 0.3mg/kg-3.0 mg/kg doses. 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 hyperoxia challenge by measuring cytotoxicity, inflammatory and anti-inflammatory mediators and macrophages; and (3) Determine toxicokinetic parameters in juvenile rats 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.

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研究公司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。我们的主要候选物AVR-48与TLR 4结合，导致选择性激活靶细胞以阻断肺中的炎症介质和上调内源性血管化途径改善肺血管化，从而改善肺功能。AVR-48具有葡糖胺核心，使其响应于肺蛋白丝氨酸/苏氨酸的O-GlcNAc化，这是一种保守的防御损伤，使细胞重塑。此外，它还能增强某些宿主抗- 炎性分子如IL-10和生长因子VEGF与血管形成作用保持局部，肺我们已经证明，腹腔注射AVR-48可以预防高氧诱导的BPD，新生小鼠幼鼠模型以10 mg/kg剂量静脉注射有创机械呼吸机诱导 0.3 mg/kg-3.0 mg/kg剂量下早产羔羊的BPD。为了推进领先的候选AVR-48，AyuVis正在提出了三个补充目标：（1）通过以下方式确定早产羔羊模型的安全性和长期有效性：测试AVR-48的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）证明通过测量细胞毒性，在高氧激发后，AVR-48在人脐带血中的抗炎作用，炎症和抗炎介质和巨噬细胞;和（3）确定毒代动力学参数幼龄大鼠，将用于模拟临床人体等效剂量。预计这些研究将提供能够使AVR-48进入GMP生产的机制和确证性有效性数据，提交新药研究申请。