ApoE4-targeted therapeutics that normalize SirT1

使 SirT1 正常化的 ApoE4 靶向疗法

• 批准号: 8988211
• 负责人: Varghese John
• 金额: $ 51.24万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-15 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8988211
• 关键词: 19q13; Address; Affect; Affinity; Alleles; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease risk; American; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Apolipoprotein E; Apoptosis; Binding; Biological Assay; Biological Markers; Brain; Caspase; Cell Line; Cell model; Cells; Chemicals; Clinical; Clinical Trials; Collaborations; Data; Development; Disease; Disease Progression; Dose; Drug Kinetics; Enhancers; Enzyme-Linked Immunosorbent Assay; Evaluation; Future; Genotype; Goals; In Vitro; Individual; Inflammation Mediators; Knowledge; Late Onset Alzheimer Disease; Lead; Learning; Libraries; Light; Link; Longevity; Mediating; Mediator of activation protein; Memory; Memory Loss; Molecular; Neurites; Neurons; Oral; Pathway interactions; Patients; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phosphorylation; Plasma; Play; Preclinical Testing; Preventive; Process; Production; Property; Proteins; Relative (related person); Reporting; Research; Risk; Risk Factors; Role; Sampling; Serum; Signal Transduction; Sirtuins; Site; Societies; Structure; Synapses; Testing; Therapeutic; Time; Toxic effect; Toxicity Tests; aging brain; amyloid pathology; amyloid precursor protein processing; analog; apolipoprotein E-2; apolipoprotein E-3; cost; design; disease phenotype; disorder risk; drug candidate; drug discovery; efficacy testing; genetic risk factor; improved; in vivo; inhibitor/antagonist; insight; longevity gene; meetings; mild cognitive impairment; mouse model; nervous system disorder; neuron loss; neurotoxic; neurotoxicity; new therapeutic target; novel; overexpression; pre-clinical; programs; public health relevance; research clinical testing; screening; tau Proteins; tau phosphorylation; therapeutic development; therapeutic target; tool development; transgenic model of alzheimer disease; uptake

 DESCRIPTION (provided by applicant): Our studies link for the first time the major risk factor for Alzheimer's disease - ApoE4 - with major longevity determinants, the Sirtuins; and identify the first candidate therapeutics that target this new link. Alzheimer's disease (AD) currently afflicts more than 5.4 million people in the US at an estimated cost to society of greater than $200 billion per year. The currently approved drugs for AD provide only short-term symptomatic relief but do not alter disease progression. The dominant risk factor for Alzheimer's disease (AD) is the epsilon-4 (e4) allele of apolipoprotein E (ApoE4), which is present in about two-thirds of AD patients. The ApoE4 allele (chromosomal locus 19q13) confers increased risk for sporadic and late-onset AD (LOAD). Despite over a decade of knowledge that the ApoE4 allele is somehow contributory to the disease process, the precise molecular mechanisms underlying ApoE4-associated AD risk remain unclear. Our studies shed light on a novel mechanism for ApoE4-mediated toxicity and revealed a key mediator - SirT1 - that is differentially affected by ApoE4 vs. ApoE3. Interestingly, while both ApoE3 and ApoE4 bind to APP, only ApoE4 associates with nanomolar affinity (Kd ~80nM), and only ApoE4 significantly: (a) reduces the ratio of sAPPa to Aß; (b) reduces SirT1 expression, resulting in a marked reduction of SirT1 levels and in the ratio of neuroprotective SirT1 to neurotoxic SirT2; (c) triggers tau and APP phosphorylation; and (d) induces programmed cell death. In our initial screen of a clinical library we have identified a promising hit (A03) that is a repurposing candidate, is highly brain permeable, and reverses the reduction of SirT1 levels. As part of this proposal we plan to complete the preclinical testing of A03 and develop new chemical entity (NCE) analogs of A03 for further development. In addition, through screening and "hit-to-lead" optimization we plan to discover new lead candidates for further testing. The eventual goal of the proposal is to provide 1-2 candidates for non-GLP toxicity testing. Our data support the hypothesis that neuronal connectivity - influenced by the ratios of critical mediators including sAPPa:Aß, SirT2:SirT1, APP:p-APP, and tau:p-tau - is programmatically altered by ApoE4. The collaboration with the Clinical Core and the Gylys lab is important in this project, as it would provide preliminary analysis of plasma and CSF samples from ApoE genotyped patients for levels of SirT1. Such data would be extremely useful for future development of ApoE4-targeted drug candidates to clinical testing and SirT1 as a potential plasma biomarker in MCI/AD. In addition, comparing SirT1 with other biomarkers in plasma/CSF that are affected by the sirtuin/NFkB signaling is planned and would help further elucidate the role of ApoE4 in AD. The overall primary objective of this project is to identify potent, orally active, brain permeable SirT1-enhancing lead candidates that are suitable for further preclinical IND development as the first ApoE4- targeted SirT1 therapeutics for AD and to development the tools necessary to ascertain target engagement and efficacy.

 描述（由适用提供）：我们的研究链接首次是阿尔茨海默氏病-APOE4的主要危险因素 - 具有主要的寿命确定剂，即Sirtuins；并确定针对此新链接的第一个候选疗法。阿尔茨海默氏病（AD）目前以每年超过2000亿美元的社会的估计成本折磨于美国的540万人。当前批准的AD药物仅提供短期症状缓解，但不会改变疾病的进展。阿尔茨海默氏病（AD）的主要危险因素是载脂蛋白E（APOE4）的Epsilon-4（E4），它存在于大约三分之二的AD患者中。 APOE4等位基因（染色体基因座19q13）承认了弹性和晚发的AD（负载）的风险增加。尽管有十多年的了解，APOE4等位基因在某种程度上是疾病过程的贡献，但与APOE4相关的AD风险的确切分子机制尚不清楚。我们的研究阐明了APOE4介导的毒性的一种新型机制，并揭示了一个关键的介质-SIRT1-受APOE4与APOE3的影响不同。有趣的是，虽然APOE3和APOE4均与App结合，但仅APOE4与纳摩尔亲和力（KD〜80nm）相关，并且仅显着地apoE4：（a）降低了Sappa与Aß的比率； （b）降低SIRT1的表达，从而显着降低SIRT1水平，并以神经保护性SIRT1与神经毒性SIRT2的比率降低； （c）触发tau和App磷酸化； （d）诱导程序性细胞死亡。在我们的临床图书馆的初始屏幕中 我们已经确定了一个重新利用的候选者的承诺命中率（A03），它是高度可渗透的，并且可以逆转SIRT1水平的降低。作为该提案的一部分，我们计划完成A03的临床前测试，并开发A03的新化学实体（NCE）类似物，以进行进一步开发。此外，通过筛选和“命中率”优化，我们计划发现新的铅候选者进行进一步测试。该提案的事件目标是为非GLP毒性测试提供1-2个候选人。我们的数据支持以下假设：神经元连通性受到关键介体的比例，包括萨帕：Aß，aß，sirt2：sirt1，app：p -app：p -app和tau：p -tau的比率 - 由apoe4在编程上更改。与临床核心和Gylys实验室的合作在该项目中很重要，因为它将对SIRT1水平的APOE基因分型患者的血浆和CSF样品进行初步分析。此类数据对于将未来的APOE4靶向药物候选物进行临床测试和SIRT1作为MCI/AD中潜在的等离子体生物标志物的开发非常有用。此外，计划将SIRT1与受SIRTUIN/NFKB信号影响的等离子体/CSF中的其他生物标志物进行比较，并将有助于进一步阐明APOE4在AD中的作用。该项目的总体主要目标是确定适合进一步的临床前IND开发的潜在，口服，可渗透的大脑可渗透的SIRT1增强率候选者，作为第一种APOE4靶向SIRT1疗法，用于AD，并开发确定目标参与和效率所需的工具。