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

新型 HDAC6i SW-100 治疗阿尔茨海默病和其他 Tau蛋白病的研究

基本信息

批准号：
9463081
负责人：
MARCIA N GORDON
金额：
$ 39.27万
依托单位：
STARWISE THERAPEUTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9463081
关键词：
Acetylation Adverse effects Affinity Age Alzheimer&apos s Disease Ames Assay Amyloid Animals Antidepressive Agents Arthritis Asthma Atrophic Autophagocytosis Axonal Transport Back Behavioral Biological Assay Brain Brain region Brain-Derived Neurotrophic Factor Cell Nucleus Cells Charcot-Marie-Tooth Disease Chemicals Chromatin Clinic Cognition Dementia Deposition Development Disease Dose Drug Targeting Drug usage EMS1 gene Endotoxins Enzymes Family Foundations Frontotemporal Dementia Funding Gene Expression HDAC1 gene HDAC4 gene HDAC6 gene HIV Half-Life Heart Diseases Heat shock proteins Heat-Shock Proteins 90 Histologic Histone Deacetylase Histone Deacetylase Inhibitor Human Huntington gene Impaired cognition Inflammation Isoenzymes Lead Lysine Malignant Neoplasms Medical Memory Loss Microtubule Stabilization Microtubules Modality Modeling Monitor Mus Mutation Neurodegenerative Disorders Neurofibrillary Tangles Neurons Nuclear Pathology Penetration Performance Peripheral Permeability Pharmaceutical Preparations Phase Phenotype Physical condensation Population Probability Progressive Supranuclear Palsy Prosencephalon Protein Family Protein Isoforms Proteins Pulmonary Edema Rattus Research Rett Syndrome Safety Sepsis Sirtuins Stroke Syndrome Tauopathies Testing Therapeutic Tissues Tubulin Validation Work amyloid pathology analog antitumor agent axonopathy cancer therapy care systems cell transformation cost depression model design effective therapy enzyme activity improved improved outcome inhibitor/antagonist mouse model multicatalytic endopeptidase complex mutant neurochemistry prevent programs research clinical testing success tau Proteins tau aggregation trafficking

项目摘要

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.

抽象的阿尔茨海默氏症和其他 tau蛋白病是日益严重的医学问题，威胁着人类的长期健康。全球医疗保健系统的长期生存能力。如今，阿尔茨海默病造成的费用占美国 GDP 的 1.2%，并且还在不断增长随着人口老龄化。有效的疾病缓解疗法尚未开发出来。多种药物在临床测试针对淀粉样蛋白，但很少有针对 tau 蛋白的研究。我们预计，就像心脏病一样，癌症和艾滋病毒，有效的阿尔茨海默病管理需要使用多种治疗方法进行联合治疗方式。我们的研究团队之前的工作已经确定，可以使用以下方法减少部分 tau 表型组蛋白脱乙酰酶 6 (HDAC6) 抑制剂，图巴他汀 A (TA)。这涉及对 Tg4510 小鼠的治疗 3个月时tau蛋白沉积形成，6个月时前脑萎缩。我们对 5 至 7 个月大的小鼠进行治疗，发现改善行为表现并减少总 tau 沉积。然而，tau 蛋白的其他成分该模型中的表型没有受到显着影响。这里我们建议测试一下改进的HDAC6是否抑制剂 SW-100 可以更彻底地挽救该小鼠的 tau 表型。 SW-100具有较高的亲和力，与 TA 相比，半衰期稍长，脑通透性显着增加。 SW-100是一种新型HDAC6抑制剂选择性与 TA 相似，但增加了 CNS 渗透性。 SW-100 进一步缺乏致突变性艾姆斯试验（TA 呈阳性）。因此，我们希望评估这种化合物以及新设计的备份模拟，可以通过追求以下三个目标来更全面地逆转 Tg4510 小鼠的表型。目的 1. 制备 4 个新的 SW-100 类似物作为潜在的备用化合物，并进行 HDAC 同工酶测试，微管蛋白乙酰化测定和 ADMET 测定。将其中最好的成果推进到目标 2 的动物研究中。目标 2. 对 SW-100 和目标 1 中的最佳备用化合物进行剂量范围寻找研究，以确定剂量在小鼠饲料中，对中枢神经系统的影响最大，并且耐受性良好。目标 3. 从两个年龄开始在 Tg4510 小鼠中测试 SW-100 和目标 1 的备用类似物，以确定程度这些新的化学实体可以阻碍 tau 表型的发展，以及是否可以带来好处即使在 tau 沉积开始后也能观察到。因此将评估药物对认知的影响，组织学 tau 沉积和神经化学 tau 积累。使用这些药物观察到的任何积极作用 tau 沉积后表明对已经患有痴呆症的人有益。 HDAC6 可以通过多种潜在机制产生益处。首先，它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，可能通过增加 HSP90 乙酰化来增加蛋白酶体中 tau 蛋白的降解。第三，它可能抑制tau蛋白通过增加 tau 乙酰化而聚集。我们将监测每种 HDAC6 底物的乙酰化开始了解该模型中对 tau 表型最有利的机制。