Study of the New HDAC6i SW-100 as a Treatment for Alzheimer’s Disease and Other Tauopathies

摘要 阿尔茨海默氏症和其他肌萎缩侧索硬化症是日益严重的医学问题，威胁着 全球医疗保健系统的长期生存能力。阿尔茨海默氏症的成本目前占美国GDP的1.2%，而且还在不断增长 随着人口老龄化。有效的疾病修正疗法尚未开发出来。在中国的一些毒品 临床检测以淀粉样蛋白为靶点，但针对tau的研究很少。我们预计，就像心脏病一样， 癌症和艾滋病毒，有效的阿尔茨海默氏症治疗将需要使用多种治疗方法的联合治疗 医疗模式。我们的研究团队之前的工作已经确定，部分tau表型可以使用 组蛋白脱乙酰酶6(HDAC6)抑制剂Tubasatin A(TA)。这涉及到对Tg4510小鼠的治疗 3个月龄形成tau沉积，6个月龄前脑萎缩。我们从5个月到7个月对老鼠进行治疗，发现 改善了行为表现，减少了总的牛磺酸沉积。然而，tau的其他成分 该模型中的表型没有受到明显影响。在这里，我们建议测试改进的HDAC6 抑制剂SW-100可以更完全地挽救该小鼠的tau表型。SW-100具有更高的亲和力， 与TA相比，半衰期略长，脑渗透性显著增加。SW-100是一种新型的HDAC6抑制剂 选择性与TA相似，但增加了中枢神经系统的渗透性。Sw-100进一步缺乏致突变性 Ames试验(TA阳性)。因此，我们希望评估这种化合物以及新设计的 后备类似物，通过追求以下三个目的，可以更全面地逆转Tg4510小鼠的表型。 目的1.制备4个新的SW-100类似物作为潜在的后备化合物，并进行HDAC同工酶检测， 微管蛋白乙酰化试验和ADMET试验。将其中最好的部分推进到《目标2》的动物研究中。 目的2.进行Sw-100和目标1的最佳后备化合物的剂量范围查找研究，以确定剂量 在小鼠食物中，它会引起最大的中枢神经系统影响，并且耐受性很好。 目的3.从两岁开始在Tg4510小鼠身上测试Sw-100和来自Aim 1的备用类似物，以确定程度 这些新的化学物质可以延缓tau表型的发展，以及是否可以受益 即使在tau沉积开始后也能观察到。因此，将对药物对认知的影响进行评估， 组织学tau沉积和神经化学tau蓄积。使用这些药物观察到的任何积极作用 在tau沉积之后，对已经患有痴呆症的人来说是有好处的。 HDAC6可通过几种潜在机制产生效益。首先，这可能会导致 更稳定的微管，并通过增加微管蛋白乙酰化来增强轴突运输。其次，它可能 通过增加HSP90乙酰化，增加蛋白酶体中tau的降解。第三，它可能会抑制tau 通过增加tau乙酰化而聚集。我们将监测每种HDAC6底物的乙酰化 为了开始了解在这个模型中对tau表型最有责任的机制(S)。

ABSTRACT Alzheimer's and other tauopathies are medical problems growing to historical proportions that threaten the long term viability of medical care systems world-wide. Alzheimer's costs today are 1.2% of the US GDP, and growing as the population ages. Effective disease-modifying treatments have yet to be developed. A number of drugs in clinical testing target amyloid, but very few have been developed to target tau. We expect that like heart disease, cancer and HIV, effective Alzheimer's management will require combination treatment using multiple therapeutic modalities. Prior work by our research team has determined that part of the tau phenotype can be reduced using a histone deacetylase 6 (HDAC6) inhibitor, Tubastatin A (TA). This involved treatment of Tg4510 mice that develop tau deposits by 3 mo and forebrain atrophy by 6 mo of age. We treated mice from 5 to 7 mo and found improved behavioral performance and reduced total tau deposition. However, other components of the tau phenotype in this model were not significantly impacted. Here we propose to test whether an improved HDAC6 inhibitor, SW-100, can more completely rescue the tau phenotype in this mouse. SW-100 has a higher affinity, slightly longer half-life and substantially increased brain permeability than TA. SW-100 is a new HDAC6 inhibitor with selectivity similar to that of TA, but increased CNS penetration. SW-100 further lacks mutagenicity in the Ames test (in which TA was positive). Thus, we wish to evaluate if this compound, as well as a newly designed back-up analog, can more fully reverse the phenotype of the Tg4510 mouse by pursuing the three aims below. Aim 1. Prepare 4 new analogs of SW-100 as potential back-up compounds, and conduct HDAC isozyme testing, tubulin acetylation assays, and ADMET assays. Advance the best of these to animal studies in Aim 2. Aim 2. Conduct a dose range finding study of SW-100 and the best back-up compound from Aim 1 to identify a dose in mouse chow that causes maximal CNS impact and is well tolerated. Aim 3. Test SW-100 and the back-up analog from Aim 1 in Tg4510 mice starting at two ages to ascertain the extent to which these new chemical entities can retard the development of the tau phenotype, and whether benefits can be observed even after tau deposition has started. Assessments will thus be made of drug effects on cognition, histological tau deposition, and neurochemical tau accumulation. Any positive effects observed using these drugs after tau deposition would suggest benefit for people who already have dementia. There are several potential mechanisms by which HDAC6 may produce benefits. First, it may lead to more stable microtubules and enhance axonal transport through increased tubulin acetylation. Second, it may increase tau degradation in the proteasome through increased HSP90 acetylation. Third, it may inhibit tau aggregation through increased tau acetylation. We will monitor acetylation of each of these HDAC6 substrates to begin understanding the mechanism(s) most responsible for benefiting the tau phenotype in this model.