Spleen tyrosine kinase as a new target for Alzheimer's Disease
脾酪氨酸激酶作为阿尔茨海默病的新靶点
基本信息
- 批准号:9206880
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-01-01 至 2019-12-31
- 项目状态:已结题
- 来源:
- 关键词:Abeta synthesisAcuteAdverse effectsAgeAgreementAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAmyloidAmyloid beta-ProteinAmyloidosisAnimal ModelAnimalsAutomobile DrivingBehaviorBehavioralBiochemicalBiochemistryBrainCenters for Disease Control and Prevention (U.S.)Cessation of lifeChronicClinicalClinical TrialsComplexDataDevelopmentDihydropyridinesDiseaseDrug CombinationsDrug TargetingEarly InterventionElementsEquilibriumEuropeEvaluationEventFailureFutureHumanInflammationInflammatoryInterventionLinkMalignant NeoplasmsManuscriptsModelingModern 1601-historyMotorMotor ActivityMusNF-kappa BNeuronal DysfunctionOutcomeParis, FrancePathologicPathologic ProcessesPathologyPerformancePharmaceutical PreparationsPhase III Clinical TrialsPhosphorylationPhosphotransferasesPre-Clinical ModelPreclinical Drug EvaluationProductionResearchSYK geneSolubilitySpleen DevelopmentTauopathiesTestingTherapeuticTimeTransgenic ModelVaccinesValidationVeteransamyloid pathologybeta-site APP cleaving enzyme 1clinical developmentcytokinedrug developmentdrug testingeffective therapyin vivointerestkinase inhibitormanmortalitymouse modelneurobehavioralneuron lossnovel strategiesnovel therapeuticspre-clinicalpreclinical trialpublic health relevancesingle moleculetau Proteinstau aggregationtau phosphorylationtau-1treatment effect
项目摘要
DESCRIPTION (provided by applicant):
This proposal presents a strategy to oppose, by inhibition of a single molecule, the three key pathologies of Alzheimer's Disease (AD): namely Aß/amyloid accumulation, tau hyperphosphorylation/aggregation and inflammation. A dichotomy has arisen in AD research over the past decade between understanding the origins of the disease and finding treatments for it. Even though there is general agreement that Aß/amyloid accumulation is an early event, drugs and vaccines aimed solely at reducing Aß/amyloid accumulation have, to date, been unsuccessful at reaching their primary clinical objectives in human trials. In several of these trials, failure was most likely due to intervention in mild or moderate disease, when tau and inflammation are driving neuronal dysfunction and death. In order to continue to target mild/moderate AD it is likely that future treatments may include a combination of drugs that target each of these pathologies and that they will be used together in a cocktail. That scenario may be decades away however, because no effective treatments have been currently approved as disease modifiers for any of these pathologies. An alternative immediate strategy is to development drugs that target all three pathologies simultaneously. This approach, if successful in preclinical and clinical trials, has the great advantage of requiring only one FDA approval rather than one for each of the drugs targeting each of the pathologies. In addition, the modern history of drug development is to target a single molecule rather than many. Both the FDA and major drug companies are comfortable with this approach because side-effects are generally related to the number of targets engaged by a therapeutic molecule. Thus, the engagement of a single target molecule with multiple beneficial downstream effects is desirable from both drug development and regulatory stand points. We have pursued this strategy by first screening for drugs that lower Aß production, which led us to the discovery of specific dihydropyridines, one of which, nilvadipine, we have now advanced to phase III clinical trials in Europe. In pursuing the mechanism of action of nilvadipine and related Aß-lowering compounds, we discovered their ability to modestly inhibit spleen tyrosine kinase (Syk) and by this mechanism to inhibit: 1) kinase cascades; 2) NF-kB activation; 3) cytokine production; 4) BACE expression and hence; 5) Aß production. As Syk was known to directly phosphorylate tau we were interested in the impact of Syk inhibition on tauopathy in relation to AD and have shown that Syk inhibition directly and indirectly reduces tau hyperphosphorylation and also lowers its aggregation. Thus our preliminary data suggest that Syk inhibition reduces three key features of AD; Aß/amyloid accumulation, tau hyperphosphorylation/aggregation and inflammation in acute treatment paradigms. The purpose of this proposal is to extend these preliminary findings to chronic studies of the impact of potent Syk inhibition on these three pathologies as a proof of concept study. We will use a highly specific Syk inhibitor in transgenic models of Alzheimer's amyloidosis and of tauopathy, both of which have prominent inflammatory features. We wish to examine these pathologies separately at this stage, in order to not confound testing of mechanistic hypotheses by making the models too complex. We have also chosen to intervene in the models once AD related pathologies are well established as we anticipate clinical use of Syk inhibitors in AD in the mild/moderate stage, when many cases of AD present in non specialist centers. We anticipate that we will see highly significant reductions of the known degenerative, inflammatory and behavioral endpoints in these models. These studies will provide the cornerstone for clinical development of Syk inhibitors for the treatment of AD.
描述(由申请人提供):
该提案提出了一种策略,通过抑制单个分子来对抗阿尔茨海默病 (AD) 的三种关键病理:即 Aß/淀粉样蛋白积累、tau 蛋白过度磷酸化/聚集和炎症。在过去的十年中,AD 研究中出现了二分法。尽管人们普遍认为 Aß/淀粉样蛋白积累是一个早期事件,但药物和疫苗的目的只是减少 Aß/淀粉样蛋白积累。迄今为止,在人体试验中未能成功实现其主要临床目标,在其中一些试验中,失败很可能是由于对轻度或中度疾病的干预,此时 tau 蛋白和炎症正在导致神经元功能障碍和死亡。继续针对轻度/中度 AD,未来的治疗可能包括针对每种病理的药物组合,并且它们将在鸡尾酒中一起使用,但是这种情况可能需要几十年的时间,因为还没有有效的治疗方法。目前被批准作为任何这些疾病的疾病调节剂另一种直接策略是开发同时针对所有三种病理的药物,如果在临床前和临床试验中取得成功,则具有巨大的优势,即只需要 FDA 批准一次,而不是针对每种疾病的每种药物都需要批准。此外,药物开发的现代历史是针对单个分子而不是多个分子,FDA 和主要制药公司都对这种方法感到满意,因为副作用通常与治疗分子所涉及的靶点数量有关。 .因此,单一目标的交战从药物开发和监管的角度来看,具有多种有益下游效应的分子是可取的,我们通过首先筛选降低 Aß 产生的药物来追求这一策略,这使我们发现了特定的二氢吡啶,其中之一是尼伐地平。现已在欧洲进入 III 期临床试验,在研究尼伐地平和相关降 Aß 化合物的作用机制时,我们发现它们具有适度抑制脾酪氨酸激酶 (Syk) 的能力,并通过这种机制可以抑制:1) 激酶级联;3) 细胞因子的产生;4) BACE 的表达;5) 由于 Syk 可以直接磷酸化 tau,我们对 Syk 的影响很感兴趣。抑制与 AD 相关的 tau 蛋白病,并表明 Syk 抑制直接和间接减少 tau 过度磷酸化,并降低其聚集。因此,我们的初步数据表明 Syk 抑制减少了 tau 蛋白的过度磷酸化。 AD 的三个关键特征;急性治疗范例中的 Aß/淀粉样蛋白积累、tau 蛋白过度磷酸化/聚集和炎症 本提案的目的是将这些初步发现扩展到有效 Syk 抑制对这三种病理的影响的长期研究中。我们将在阿尔茨海默病淀粉样变性和 tau 蛋白病的转基因模型中使用高度特异性的 Syk 抑制剂,这两种疾病都具有显着的炎症特征,我们希望在此阶段分别检查这些病理学。为了不使模型过于复杂而混淆机制假设的测试,我们还选择在 AD 相关病理明确后对模型进行干预,因为我们预计 Syk 抑制剂在轻度/中度阶段的临床应用。 ,当许多 AD 病例出现在非专科中心时,我们预计我们将在这些模型中看到已知的退行性、炎症和终点的高度行为显着减少,这些研究将为 Syk 抑制剂的临床开发奠定基础。广告。
项目成果
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