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tauopathies是医疗问题，发展到历史比例，威胁到长期全球医疗系统的术语生存能力。当今阿尔茨海默氏症的费用占美国GDP的1.2％，并且增长随着人口的年龄。有效的疾病改良治疗尚未开发。许多药物临床测试靶淀粉样蛋白，但很少开发用于靶向tau。我们希望像心脏病一样癌症和艾滋病毒，有效的阿尔茨海默氏症的管理将需要使用多种治疗方式。我们的研究团队的先前工作已经确定可以使用一部分tau表型减少组蛋白脱乙酰基酶6（HDAC6）抑制剂Tubastatin A（TA）。这涉及对TG4510小鼠的治疗将Tau沉积物通过3个月和前脑萎缩开发6个月。我们将小鼠从5到7个月治疗，发现改善行为性能并减少TAU的总沉积。但是，tau的其他组件该模型中的表型没有受到显着影响。在这里，我们建议测试改进的HDAC6 抑制剂SW-100可以更彻底地挽救该小鼠中的Tau表型。 SW-100具有更高的亲和力，半衰期略长，大脑渗透性大大增加了。 SW-100是一种新的HDAC6抑制剂选择性与TA相似，但CNS渗透增加。 SW-100进一步缺乏诱变 AMES测试（其中TA为正）。因此，我们希望评估这种化合物以及新设计的备份类似物可以通过追求下面的三个目标来更全面地逆转TG4510鼠标的表型。 AIM 1。准备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，即微管蛋白乙酰化测定和ADMET分析。在AIM 2中将这些中的最好的方法推向动物研究。 AIM 2。进行SW-100的剂量范围查找研究和AIM 1的最佳备份化合物以识别剂量在小鼠CHOW中，会引起最大CNS撞击并且耐受性良好。 AIM 3。测试SW-100和TG4510小鼠AIM 1的备份类似物，以确定程度这些新化学实体可以阻止tau表型的发展，以及利益是否可以是即使在Tau沉积开始后也观察到。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影响在Tau沉积之后，将为已经患有痴呆症的人提供好处。 HDAC6有几种潜在的机制可能会产生好处。首先，它可能导致通过增加的微管蛋白乙酰化，更稳定的微管和增强轴突转运。其次，它可能通过增加的Hsp90乙酰化来增加蛋白酶体中的tau降解。第三，它可能会抑制tau 通过增加tau乙酰化的聚集。我们将监视这些HDAC6底物的乙酰化开始理解该模型中最大程度地使Tau表型受益的机制。