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,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。我们的主要候选AVR-48与TLR4绑定,从而
靶细胞选择性激活阻断肺内炎性介质及上调内源性激素
血管形成途径改善肺血管形成,从而改善肺功能。AVR-48有一个
氨基葡萄糖核心,使其对肺蛋白的丝氨酸/苏氨酸的O-GlcN酰化反应,一个保守的
对损伤的防御,使细胞重塑。此外,它还能提高某些寄主抗病原的产量。
IL-10和生长因子血管内皮生长因子等炎症分子对血管形成的影响仍局限于
肺部。我们已经证明,腹膜腔内注射AVR-48可以预防高氧诱导的BPD。
10 mg/kg剂量和静脉注射有创机械呼吸机诱导的新生小鼠幼鼠模型
早产羔羊BPD剂量为0.3 mg/kg-3.0 mg/kg。为了推进领先的候选AVR-48,AyuVis
提出三个相辅相成的目标:(1)确定早产羔羊模型的安全性和长期疗效
测试AVR-48预防性治疗是否能改善长期呼吸、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
用细胞毒实验检测AVR-48对高氧攻击后人脐血的抗炎作用
炎症和抗炎介质和巨噬细胞;以及(3)测定毒代动力学参数。
幼年大鼠,将被用来在临床上模拟人的等量剂量。这些研究有望提供
机械和确凿的功效数据,使AVR-48能够进入GMP生产和
提交一份研究用新药申请。
项目成果
期刊论文数量(0)
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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: