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。
基本信息
- 批准号:9134606
- 负责人:
- 金额:$ 74.46万
- 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 2017-09-14
- 项目状态:已结题
- 来源:
- 关键词:AcuteAddressAdverse effectsAffectAlzheimer&aposs DiseaseAmes AssayAmyloidAmyloid beta-ProteinBrainCanis familiarisCardiovascular systemCellsChromosome abnormalityChronicClinicalClinical ResearchClinical TrialsDataDiseaseDisease ProgressionDoseDrug KineticsDrug or chemical Tissue DistributionEquilibriumEtiologyEvaluationExcretory functionFDA approvedFailureFunctional disorderGoalsGuidelinesHealthHepatocyteHumanImmuneImmune systemImpaired cognitionIn VitroInterventionInvestigational DrugsInvestigational New Drug ApplicationLeadManuscriptsMaximum Tolerated DoseMeasuresMediator of activation proteinMetabolismMolecular TargetMorbidity - disease rateMusMutationNerve DegenerationNeurodegenerative DisordersNeurofibrillary TanglesNeurologicNeuroprotective AgentsOralOral AdministrationPathologyPatientsPeripheralPharmaceutical PreparationsPharmacologyPharmacotherapyPhasePhase III Clinical TrialsProgress ReportsProteinsRadioactivityRadiolabeledRattusReportingResearchResearch DesignSafetySenile PlaquesSmall Business Innovation Research GrantStaining methodStainsSymptomsSynapsesTNF geneTestingTherapeuticTherapeutic IndexThioflavin SToxic effectToxicologyTransgenic OrganismsTreatment Protocolsabsorptionamyloid precursor protein processingclinically significantcognitive functioncytokinedrug candidategenotoxicityimprovedin vivoinhibitor/antagonistmalemanmeetingsmetabolic profilemortalitymouse modelneuroinflammationneuron lossneuropathologyneurotoxicneurotoxicitynovelphase 1 studypreclinical studyradiotracerrespiratoryresponsesmall moleculesymptom treatmenttau Proteinstau phosphorylation
项目摘要
DESCRIPTION (provided by applicant): The goal of this proposal is to develop tumor necrosis factor a (TNFa)-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-a as a key mediator in AD- associated neurodegenerative pathology. Multiple preclinical and clinical studies indicate that TNFa is a "druggable" molecular target to modify the course of AD progression. Preliminary Studies demonstrate that our lead compound, IDT, shows potent TNFa inhibition in vitro. Our Phase 1 SBIR studies demonstrate that a low dose of IDT administered orally every day for 10 months significantly improved cognitive function in the triple-transgenic (3xTg) AD mouse model. IDT also modulated brain TNFa protein levels and halted the progress of AD- associated neuropathology including Aß plaques and neurofibrally 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 IDT. Taken together, these data strongly suggest that our lead compound is an excellent anti-AD drug candidate. The proposed Phase 2 SBIR studies are designed to achieve two goals. First, we want to conduct the FDA safety and toxicology studies required for submission of IDT as an Investigational New Drug (IND) application which would allow its use in humans when approved (Aims 1-4). Second, our efficacy data suggests IDT may be more effective at an even lower dose. Aim 5 will optimize IDT dose-efficacy response at lower doses in 3xTgAD mice. Aim 1: Assess IDT genotoxicity. Aim 2: Assess IDT absorption, distribution, metabolism and excretion (ADME) Aim 3: Assess oral IDT safety pharmacology in three studies: Aim 4: Assess repeated IDT dose toxicity in rats. Aim 5: Assess lower IDT doses in 3xTg AD mice.
描述(由申请人提供):本提案的目标是开发肿瘤坏死因子a(TNF α)抑制化合物作为治疗阿尔茨海默病(AD)的神经保护药物。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过程。因此,迫切需要针对AD病理生理学的新型AD治疗。最近的研究表明神经炎性细胞因子TNF-α是AD相关神经退行性病理学中的关键介质。多项临床前和临床研究表明,TNF α是一种“可药物化”的分子靶点,可以改变AD的进展过程。初步研究表明,我们的先导化合物IDT在体外显示出有效的TNF α抑制作用。我们的1期SBIR研究表明,每天口服低剂量IDT持续10个月显著改善了三转基因(3xTg)AD小鼠模型的认知功能。IDT还调节脑TNF α蛋白水平,并阻止AD相关神经病理学的进展,包括通过免疫组织学染色评估的斑块和神经纤维缠结。尽管长期每日口服IDT治疗方案,但未观察到发病率、死亡率或任何明显的副作用。总之,这些数据有力地表明,我们的先导化合物是一个很好的抗AD候选药物。拟定的2期SBIR研究旨在实现两个目标。首先,我们希望进行IDT作为研究性新药(IND)申请提交所需的FDA安全性和毒理学研究,以便在批准后允许其用于人类(目标1-4)。其次,我们的疗效数据表明IDT在更低的剂量下可能更有效。目的5将在3xTgAD小鼠中以较低剂量优化IDT剂量-功效反应。目的1:评估IDT的遗传毒性。目标二:评估IDT的吸收、分布、代谢和排泄(ADME)目的3:在三项研究中评估口服IDT的安全药理学:目的4:评估大鼠中IDT的重复给药毒性。目的5:评估3xTg AD小鼠中的较低IDT剂量。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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