A Novel Small Molecule TNF-alpha Inhibitor as a Disease-Modifying Alzheimer's Disease Drug Treatment
一种新型小分子 TNF-α 抑制剂作为缓解阿尔茨海默病药物治疗的药物
基本信息
- 批准号:9466541
- 负责人:
- 金额:$ 69.69万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-09-01 至 2020-05-31
- 项目状态:已结题
- 来源:
- 关键词:ADME StudyAcuteAddressAdverse effectsAffectAlzheimer&aposs DiseaseAmyloidAmyloid beta-ProteinAnimalsAreaAwardBackBrain NeoplasmsCanis familiarisCardiovascular systemCharacteristicsChronicClinicalClinical ResearchCognitionDataDevelopment PlansDiseaseDisease ProgressionDoseDrug TargetingElementsEtiologyExcretory functionFDA approvedFailureFrontotemporal DementiaFunctional disorderFutureGoalsGrantGuidelinesHumanIn VitroInterventionInvestigational DrugsInvestigational New Drug ApplicationLeadLicensingMeasuresMediator of activation proteinMetabolismMolecular TargetMorbidity - disease rateMusNerve DegenerationNeurodegenerative DisordersNeurofibrillary TanglesNeurologicNeuroprotective AgentsNo-Observed-Adverse-Effect LevelOralOryctolagus cuniculusPathologyPatientsPharmaceutical PreparationsPharmacotherapyPhasePhase III Clinical TrialsPilot ProjectsPreparationProteinsPublishingRattusReadinessReportingResearchSafetySmall Business Innovation Research GrantStaining methodStainsSuggestionSymptomsTNF geneTelemetryTherapeuticThioflavin SToxicologyTransgenic OrganismsTreatment Protocolsabsorptionbaseclinical developmentcognitive functioncytokinedevelopmental toxicologydrug candidatedrug developmentefficacy studyfactor Agood laboratory practiceimprovedinhibitor/antagonistmeetingsmetabolic abnormality assessmentmortalitymouse modelneuroinflammationneuropathologynovelpre-clinicalpreclinical studysafety studysafety testingsmall moleculesymptom treatmenttau phosphorylationtrendtumor necrosis factor-alpha inhibitor
项目摘要
ABSTRACT
The goal of this proposal is to develop tumor necrosis factor α (TNFα)-inhibiting compounds as
neuroprotectant drugs for treating Alzheimer’s disease (AD). Current FDA-approved AD
interventions are symptomatic treatments with limited efficacy which do not affect AD etiology or
modify the course of disease progression. Thus, a critical need exists for a novel AD treatment
directed towards AD pathophysiology.
Recent studies implicate the neuroinflammatory cytokine TNF-α as a key mediator in AD-
associated neurodegenerative pathology. Multiple preclinical and clinical studies indicate that
TNFα is a “druggable” molecular target to modify the course of AD progression.
Preliminary Studies demonstrate that our lead compound shows potent TNFα inhibition in vitro.
Our Phase 1 SBIR studies demonstrate that our small molecule TNFα inhibitor administered
orally every day for 10 months significantly improved cognitive function in the triple-transgenic
(3xTg) AD mouse model. Our compound also modulated brain TNFα protein levels and halted
the progress of AD-associated neuropathology including Aß plaques and neurofibrillary tangles
as assessed by immunohistological staining. No morbidity, mortality or any obvious side effects
were observed despite the long-term oral daily treatment regimen with our compound. Taken
together, these data strongly suggest that our lead compound is an excellent anti-AD drug
candidate. The proposed studies are following up on recently awarded phase 2 SBIR where we
are performing several key FDA-required IND studies. The proposed CRP grant studies will
build on the phase 2 SBIR studies to lead to an IND submission. Key Aims include large animal
safety toxicology studies and preparation for Pre-IND meeting with the FDA.
摘要
该提案的目标是开发肿瘤坏死因子α(TNFα)抑制化合物,
用于治疗阿尔茨海默病(AD)的神经保护剂药物。目前FDA批准的AD
干预措施是疗效有限的对症治疗,不影响AD病因,或
改变疾病进展的进程。因此,迫切需要一种新的AD治疗
针对AD病理生理学。
最近的研究表明,神经炎性细胞因子TNF-α是AD的关键介质,
相关的神经退行性病变。多项临床前和临床研究表明,
TNFα是一种“可药物化”的分子靶点,可改变AD进展的进程。
初步研究表明,我们的先导化合物在体外显示出有效的TNFα抑制作用。
我们的1期SBIR研究表明,我们的小分子TNFα抑制剂
每天口服10个月,显著改善了三转基因小鼠的认知功能。
(3xTg)AD小鼠模型。我们的化合物还调节脑TNFα蛋白水平,
AD相关神经病理学研究进展,包括斑块和神经纤维缠结
如通过免疫组织学染色评估的。无发病率、死亡率或任何明显副作用
尽管长期口服每日治疗方案与我们的化合物观察。采取
总之,这些数据有力地表明,我们的先导化合物是一种很好的抗AD药物
候选人拟议的研究是对最近授予的第2阶段SBIR的后续研究,
正在进行几项FDA要求的关键IND研究。拟议的CRP赠款研究将
在2期SBIR研究的基础上进行IND申报。主要目标包括大型动物
安全性毒理学研究和准备与FDA的Pre-IND会议。
项目成果
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专利数量(0)
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{{ truncateString('SOMASUNDAR PRASAD GABBITA', 18)}}的其他基金
Targeting Latexin for radiation mitigation.
针对 Latexin 进行辐射缓解。
- 批准号:
9925204 - 财政年份:2019
- 资助金额:
$ 69.69万 - 项目类别:
A Novel Small molecule TNF-alpha inhibitor as a disease-modifying AD drug treatment.
一种新型小分子 TNF-α 抑制剂作为缓解疾病的 AD 药物治疗。
- 批准号:
8980560 - 财政年份:2015
- 资助金额:
$ 69.69万 - 项目类别:
A Novel Small molecule TNF-alpha inhibitor as a disease-modifying AD drug treatment.
一种新型小分子 TNF-α 抑制剂作为缓解疾病的 AD 药物治疗。
- 批准号:
9134606 - 财政年份:2015
- 资助金额:
$ 69.69万 - 项目类别:
A first-in-class orally active anti-TNF-alpha inhibitor to treat AD
治疗 AD 的一流口服活性抗 TNF-α 抑制剂
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8592209 - 财政年份:2013
- 资助金额:
$ 69.69万 - 项目类别:
A rapid microfluidic P.O.C CNS biomarker platform to predict delayed HICP onset.
一种快速微流体 P.O.C CNS 生物标志物平台,用于预测延迟 HICP 发作。
- 批准号:
8312928 - 财政年份:2012
- 资助金额:
$ 69.69万 - 项目类别:
PD2005: A CNS active DAT inhibitor for improving cognitive deficits in traumatic
PD2005:一种 CNS 活性 DAT 抑制剂,用于改善创伤性认知缺陷
- 批准号:
8060050 - 财政年份:2011
- 资助金额:
$ 69.69万 - 项目类别:
PD2024: A Peripherally Active TNFalpha inhibitor for the treatment of Obesity
PD2024:一种用于治疗肥胖的外周活性 TNFα 抑制剂
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8004629 - 财政年份:2010
- 资助金额:
$ 69.69万 - 项目类别:
Thiothalidomides as neuroprotectant drugs for PD.
硫沙利度胺作为 PD 的神经保护药物。
- 批准号:
7331541 - 财政年份:2007
- 资助金额:
$ 69.69万 - 项目类别:
Neuroprotective efficacy of a melatonin analog in traumatic brain injury
褪黑激素类似物对创伤性脑损伤的神经保护作用
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7053659 - 财政年份:2006
- 资助金额:
$ 69.69万 - 项目类别:
Thiothalidomides as neuroprotectants drugs for ALS
硫沙利度胺作为 ALS 的神经保护药物
- 批准号:
6994265 - 财政年份:2005
- 资助金额:
$ 69.69万 - 项目类别:
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