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:
- 金额:$ 70.21万
- 依托单位:
- 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:
- 关键词:AdolescentAdrenal Cortex HormonesAdultAffectAgreementAlveolarAngiogenic FactorAnimalsAnti-Inflammatory AgentsAntiinflammatory EffectBacteremiaBindingBolus InfusionBrainBronchopulmonary DysplasiaCalciumCardiacCardiotoxicityCell DeathCellsCessation of lifeChildhoodChitinClinicClinicalClinical TrialsComplicationDataDevelopmentDiagnosisDiseaseDoseDysplasiaEndothelial Growth FactorsEnzyme-Linked Immunosorbent AssayExposure toGasesGenetic Predisposition to DiseaseGestational AgeGoalsGram-Negative BacteriaGram-Negative Bacterial InfectionsGrantHumanHyperoxiaImmune responseImmunityImmunologistImpairmentIn VitroIncidenceInfantInfectionInflammationInflammation MediatorsInflammatoryInjectionsInterleukin-1 betaInterleukin-10Interleukin-6Intraperitoneal InjectionsInvestigational New Drug ApplicationLeadLifeLungLymphocyteMacrophageMeasuresMechanical VentilatorsMechanical ventilationModelingMolecular WeightMusNeonatalNo-Observed-Adverse-Effect LevelOligosaccharidesOrphanOutcome MeasureOxygenPathologicPathway interactionsPhagocytosisPharmaceutical PreparationsPhenotypePhysiologyPlasmaPlayPremature BirthPremature InfantPreventionPrevention approachProductionProphylactic treatmentProteinsProtocols documentationPulmonary HypertensionPulmonary InflammationRattusReactive Oxygen SpeciesRecoveryRegimenReportingResearchRespiratory DiseaseRespiratory FailureRestRiskRoleSafetyScientistSecondary toSeriesSerumSignal TransductionTLR4 geneTNF geneTechniquesTestingTherapeutic EffectTimeToxicokineticsTransforming Growth Factor betaTreatment EfficacyUmbilical Cord BloodUniversitiesUp-RegulationUtahUterusVascular Endothelial Growth FactorsVascularizationVentilatorWorkantagonistantenatalchronic respiratory diseasecomorbiditycytokinecytotoxicitydrug developmentearly childhoodefficacy testingendothelial dysfunctionexperiencegenotoxicityhuman modelimmunoregulationimprovedin vitro testingintravenous injectionlamb modellead candidatelung injurymanufacturemeetingsmonocytemouse modelneonatal miceneonateneurotensin mimic 1novelnovel strategiesnovel therapeuticsperipheral bloodpre-Investigational New Drug meetingprenatalpreterm newbornpreventprogramsprophylacticpulmonary functionpuprespiratoryresponsesmall 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. 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
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:
10765750 - 财政年份:2023
- 资助金额:
$ 70.21万 - 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:
10482142 - 财政年份:2022
- 资助金额:
$ 70.21万 - 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:
$ 70.21万 - 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:
$ 70.21万 - 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:
$ 70.21万 - 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:
$ 70.21万 - 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:
$ 70.21万 - 项目类别: