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:
- 金额:$ 20.4万
- 依托单位:
- 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:
- 关键词:AdolescentAdrenal Cortex HormonesAdultAffectAgreementAlveolarAngiogenic FactorAnimalsAnti-Inflammatory AgentsAntiinflammatory EffectBacteremiaBindingBolus InfusionBrainBronchopulmonary DysplasiaCanis familiarisCardiacCardiotoxicityCell DeathCellsCessation of lifeChildhoodChitinClinicClinicalClinical TrialsComplicationDataDevelopmentDiagnosisDiseaseDoseDysplasiaEnzyme-Linked Immunosorbent AssayExposure toGasesGenetic Predisposition to DiseaseGestational AgeGlucosamineGoalsGram-Negative BacteriaGram-Negative Bacterial InfectionsGrantGrowth FactorHumanHyperoxiaImmune responseImmunityImmunologistImpairmentIn VitroIncidenceInfantInfectionInflammationInflammation MediatorsInflammatoryInjectionsInjuryInterleukin-1 betaInterleukin-10Interleukin-6Intraperitoneal InjectionsInvestigational New Drug ApplicationLeadLifeLungLymphocyteMacrophageMeasuresMechanical VentilatorsMechanical ventilationModelingMolecular WeightMusNeonatalNeonatal Intensive Care UnitsNewborn InfantNo-Observed-Adverse-Effect LevelOligosaccharidesOrphanOutcome MeasureOxygenPathologicPathway interactionsPhagocytosisPharmaceutical PreparationsPhenotypePhysiologyPlasmaPlayPremature BirthPremature InfantPreventionPrevention approachProductionProphylactic treatmentProteinsPulmonary HypertensionPulmonary InflammationRattusRecoveryRegimenReportingResearchRespiratory DiseaseRespiratory FailureRestRiskRoleSafetyScientistSecondary toSeriesSerineSerumSignal TransductionTLR4 geneTNF geneTechniquesTestingThreonineTimeToxicokineticsTransforming Growth Factor betaTreatment EfficacyUmbilical Cord BloodUniversitiesUp-RegulationUtahUterusVascular Endothelial Growth FactorsVascularizationVentilatorWorkantagonistantenatalchronic respiratory diseasecomorbiditycytokinecytotoxicitydrug developmentearly childhoodefficacy testingendothelial dysfunctiongenotoxicityhuman modelimmunoregulationimprovedin vitro testingintravenous injectionlamb modellead candidatelung injurymanufacturemeetingsmonocytemouse modelneonatal miceneonateneurotensin mimic 1novelnovel strategiesnovel therapeuticsperipheral bloodpre-Investigational New Drug meetingprenatalpreterm newbornpreventprogramsprophylacticpulmonary functionpuprespiratorysmall moleculesurfactanttissue repairvasculogenesisventilation
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。
项目成果
期刊论文数量(0)
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Suchismita Acharya其他文献
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{{ truncateString('Suchismita Acharya', 18)}}的其他基金
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
- 批准号:
10482142 - 财政年份:2022
- 资助金额:
$ 20.4万 - 项目类别:
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
- 批准号:
10616606 - 财政年份:2022
- 资助金额:
$ 20.4万 - 项目类别:
Novel hybrid molecule with both IOP lowering and neuroprotective effects for treatment of glaucoma
具有降低眼压和神经保护作用的新型混合分子可用于治疗青光眼
- 批准号:
10477236 - 财政年份:2020
- 资助金额:
$ 20.4万 - 项目类别:
Novel hybrid molecule with both IOP lowering and neuroprotective effects for treatment of glaucoma
具有降低眼压和神经保护作用的新型混合分子可用于治疗青光眼
- 批准号:
10684092 - 财政年份:2020
- 资助金额:
$ 20.4万 - 项目类别:
Sex differences in in vitro and in vivo glaucoma models may predict gender specific dose adjustment needs
体外和体内青光眼模型的性别差异可以预测性别特异性剂量调整需求
- 批准号:
10333877 - 财政年份:2020
- 资助金额:
$ 20.4万 - 项目类别:
Novel hybrid molecule with both IOP lowering and neuroprotective effects for treatment of glaucoma
具有降低眼压和神经保护作用的新型混合分子可用于治疗青光眼
- 批准号:
10226000 - 财政年份:2020
- 资助金额:
$ 20.4万 - 项目类别:
Novel hybrid molecule with both IOP lowering and neuroprotective effects for treatment of glaucoma
具有降低眼压和神经保护作用的新型混合分子可用于治疗青光眼
- 批准号:
9887870 - 财政年份:2020
- 资助金额:
$ 20.4万 - 项目类别:














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