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

• 批准号: 9206880
• 负责人: FIONA C. CRAWFORD
• 金额: --
• 依托单位: JAMES A. HALEY VA MEDICAL CENTER
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/9206880
• 关键词: Abeta synthesis; Acute; Adverse effects; Age; Agreement; Alzheimer' s Disease; Alzheimer' s disease model; Amyloid; Amyloid beta-Protein; Amyloidosis; Animal Model; Animals; Automobile Driving; Behavior; Behavioral; Biochemical; Biochemistry; Brain; Centers for Disease Control and Prevention (U.S.); Cessation of life; Chronic; Clinical; Clinical Trials; Complex; Data; Development; Dihydropyridines; Disease; Drug Combinations; Drug Targeting; Early Intervention; Elements; Equilibrium; Europe; Evaluation; Event; Failure; Future; Human; Inflammation; Inflammatory; Intervention; Link; Malignant Neoplasms; Manuscripts; Modeling; Modern 1601-history; Motor; Motor Activity; Mus; NF-kappa B; Neuronal Dysfunction; Outcome; Paris, France; Pathologic; Pathologic Processes; Pathology; Performance; Pharmaceutical Preparations; Phase III Clinical Trials; Phosphorylation; Phosphotransferases; Pre-Clinical Model; Preclinical Drug Evaluation; Production; Research; SYK gene; Solubility; Spleen Development; Tauopathies; Testing; Therapeutic; Time; Transgenic Model; Vaccines; Validation; Veterans; amyloid pathology; beta-site APP cleaving enzyme 1; clinical development; cytokine; drug development; drug testing; effective therapy; in vivo; interest; kinase inhibitor; man; mortality; mouse model; neurobehavioral; neuron loss; novel strategies; novel therapeutics; pre-clinical; preclinical trial; public health relevance; single molecule; tau Proteins; tau aggregation; tau phosphorylation; tau-1; treatment effect

 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)： 这一建议提出了一种策略，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：A？/淀粉样蛋白积聚、tau过度磷酸化/聚集和炎症。在过去的十年里，AD的研究在了解疾病的起源和找到治疗方法之间出现了两极分化。尽管人们普遍认为A？/淀粉样蛋白积聚是一个早期事件，但迄今为止，仅旨在减少A？/淀粉样蛋白积聚的药物和疫苗在人体试验中并未成功达到它们的主要临床目标。在其中几项试验中，失败最有可能是由于对轻度或中度疾病的干预，当时tau和炎症正在导致神经元功能障碍和死亡。为了继续针对轻度/中度阿尔茨海默病，未来的治疗可能包括针对每种病理疾病的药物组合，这些药物将在鸡尾酒中一起使用。然而，这种情况可能还需要几十年的时间，因为目前还没有有效的治疗方法被批准作为这些病理的疾病修饰剂。另一种立竿见影的策略是开发同时针对这三种疾病的药物。如果在临床前和临床试验中取得成功，这种方法具有巨大的优势，即只需一次FDA批准，而不是针对每种病理疾病的每种药物都需要一次批准。此外，现代药物开发的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参与的靶点数量有关。因此，从药物开发和调控的角度来看，具有多种有益下游效应的单个靶分子的结合是可取的。我们通过首先筛选降低Aü产量的药物来推行这一策略，这导致我们发现了特定的二氢吡啶类药物，其中一种是尼尔瓦地平，我们现在已经在欧洲推进到第三阶段临床试验。在探索尼伐地平和相关的A？降低化合物的作用机制的过程中，我们发现它们能够适度抑制脾酪氨酸激酶(Syk)，并通过这个机制抑制：1)激酶级联反应；2)核因子-kB的激活；3)细胞因子的产生；4)BACE的表达，因此；5)A？的产生。由于已知Syk可以直接磷酸化tau，我们对Syk抑制对与AD相关的tau病的影响很感兴趣，并且已经证明Syk抑制直接和间接地减少tau的过度磷酸化，并降低其聚集性。因此，我们的初步数据表明，抑制Syk可以减少AD的三个关键特征：A？/淀粉样蛋白积聚、tau过度磷酸化/聚集和急性治疗范例中的炎症。这项建议的目的是将这些初步发现扩展到有效的Syk抑制对这三种病理的影响的慢性研究，作为概念研究的证据。我们将在阿尔茨海默氏症淀粉样变性和肌萎缩侧索硬化症的转基因模型中使用一种高度特异的Syk抑制剂，这两种疾病都具有显著的炎症特征。我们希望在这个阶段分别检查这些病理学，以便不因模型过于复杂而混淆机械假说的测试。我们还选择在AD相关病理建立良好后对模型进行干预，因为我们预计在轻/中度阶段使用Syk抑制剂治疗AD，届时许多AD病例出现在非专科中心。我们预计，我们将在这些模型中看到已知的退行性、炎症性和行为终结点的显著减少。这些研究将为临床开发治疗阿尔茨海默病的Syk抑制剂奠定基础。