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A Cytochrome P450 Therapeutic Space for Tauopathies

Tau蛋白病的细胞色素 P450 治疗空间

基本信息

批准号：
10461317
负责人：
Ross Leigh Cagan
金额：
$ 80.19万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-30 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10461317
关键词：
Address Alzheimer&apos s Disease Alzheimer&apos s disease patient Amyloid beta-Protein Animal Model Animals Area Aromatase Aromatase Inhibition Aromatase Inhibitors BAY 54-9085 Behavioral Biochemical Biological Assay Biology Brain Cell Line Cell physiology Cells Cellular Stress Chemicals Chemistry Cholinesterase Inhibitors Clinical Trials Complex Cytochrome P450 Cytochrome a Data Defect Development Disease Disease Progression Drosophila genus Drug Exposure Effectiveness Ensure Enzymes FDA approved Familial disease Frontotemporal Lobar Degenerations Functional disorder Goals Histologic Human Immunotherapy Impaired cognition In Situ In Vitro Induced pluripotent stem cell derived neurons Inflammation Insulin Intellectual Property Laboratories Lead MAPT gene Mass Spectrum Analysis Mediating Mediator of activation protein Memantine Metabolic Microtubules Modeling Mus Mutation NMDA receptor antagonist Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Neurons Nitriles Pathology Patients Permeability Pharmaceutical Preparations Phenotype Positron-Emission Tomography PrP gene Predisposition Progressive Supranuclear Palsy Property Protein Isoforms Series Structure Structure-Activity Relationship System Tauopathies Testing Therapeutic Therapeutic Index Toxic effect Tracer Transgenic Mice Transgenic Organisms Triazoles Work analog anastrozole appendage blood-brain barrier penetration cognitive function design experimental study fly improved induced pluripotent stem cell inhibitor/antagonist interdisciplinary approach interest lead candidate mRNA Expression mouse model novel novel lead compound targeted treatment tau Proteins tau mutation tau phosphorylation therapeutic target tool

项目摘要

A Cytochrome P450 Therapeutic Space for Tauopathies Project Summary In the 30 years since Tau was first identified as a key constituent of neurofibrillary tangles—and subsequently a causative agent of neurodegeneration—the Tauopathy field has made important strides in understanding how abnormal forms of Tau protein lead to damage. Tau interacts in complex ways with other cellular constituents and with surrounding cells within the brain. This complexity makes developing tauopathy therapeutics especially challenging. Currently there are no therapies that strongly alter disease progression: approved treatments such as cholinesterase inhibitors and the NMDA receptor antagonist memantine show modest symptomatic benefit in patients with early- to mid-stage Alzheimer’s Disease. New efforts include reducing Tau mRNA expression, reducing insulin-associated metabolic deficits, addressing abnormal Tau phosphorylation and, in recent clinical trials, targeting the spread of pathogenic Tau protein with immunotherapy. To date, these approaches have yielded limited efficacy, Pathophysiological changes in the brain precede cognitive impairment by years or even decades, presenting a broad temporal window for treatment. Tools including PET, chemical tracers and mass spectrometry assays are being developed to detect prodromal pathogenic Tau isoforms in situ. Focusing on Mendelian forms of tauopathy presents a still broader temporal window for treatment. One promising approach to reducing long-term toxicity is targeted therapies, for example against Tau protein itself. However, Tau protein is fundamental to a cell’s physiology and the therapeutic window of Tau-specific therapies may prove limited. Our laboratories are working to create an integrated approach to both understand the biology of tauopathies and to develop new lead compounds. Regarding the latter we are using the Drosophila TauR406W platform as a whole animal model to identify drugs that can reduce Tau-dependent neuronal damage. An especially promising hit is the FDA approved drug Anastrozole, an inhibitor of the cytochrome P450 Aromatase. We further demonstrated the effectiveness of Anastrozole to reduce dysfunction in an iPSC- derived TauR406W model. Remarkably, this Tau rescue did not dependent on Anastrozole’s inhibition of Aromatase, indicating Anastrozole is acting through off-target activities, suggesting the potential for an improved Anastrozole analog. We propose to use our novel fly/chemistry platform to ‘evolve’ an improved Anastrozole analog (‘anastrolog’) that better addresses Tau-mediated damage in the context of the whole animal while retaining at least some of Anastrozole’s favorable properties.

Tau蛋白病的细胞色素 P450 治疗空间项目概要自 Tau 蛋白首次被确定为神经原纤维缠结的关键成分以来的 30 年里，随后成为神经退行性变的致病因素——Tau蛋白病领域在以下方面取得了重要进展：了解 Tau 蛋白的异常形式如何导致损伤。 Tau 与其他物质以复杂的方式相互作用细胞成分以及大脑内周围的细胞。这种复杂性使得 tau 蛋白病的发展治疗尤其具有挑战性。目前没有可以强烈改变疾病进展的疗法：胆碱酯酶抑制剂和 NMDA 受体拮抗剂美金刚等已获批准的治疗方法对早期至中期阿尔茨海默病患者的症状有一定的改善。新的努力包括减少 Tau mRNA 表达，减少胰岛素相关代谢缺陷，解决异常 Tau 磷酸化，并且在最近的临床试验中，针对致病性 Tau 蛋白的传播免疫疗法。迄今为止，这些方法的效果有限，大脑的病理生理变化先于认知障碍数年甚至数十年，提供了广阔的治疗时间窗口。工具包括 PET、化学示踪剂和质量正在开发光谱测定法来原位检测前驱致病性 Tau 亚型。专注于孟德尔形式的 tau 蛋白病提供了更广泛的治疗时间窗口。一种有前途的方法减少长期毒性的方法是靶向治疗，例如针对 Tau 蛋白本身。然而，陶蛋白质是细胞生理学的基础，Tau 特异性疗法的治疗窗口可能被证明有限的。我们的实验室正在努力创建一种综合方法来了解 tau蛋白病并开发新的先导化合物。对于后者，我们使用果蝇 TauR406W 平台作为一个整体动物模型来识别可以减少 Tau 依赖性神经元损伤的药物。一个特别有前途的热门药物是 FDA 批准的药物阿那曲唑，一种细胞色素 P450 抑制剂芳香酶。我们进一步证明了阿那曲唑减少 iPSC 功能障碍的有效性衍生 TauR406W 模型。值得注意的是，这种 Tau 蛋白拯救并不依赖于阿那曲唑对芳香酶，表明阿那曲唑通过脱靶活性发挥作用，这表明阿那曲唑具有潜在的作用改进的阿那曲唑类似物。我们建议使用我们新颖的飞行/化学平台来“进化”改进的阿那曲唑类似物（“anaastrolog”）可以更好地解决整体背景下 Tau 介导的损伤动物，同时至少保留阿那曲唑的一些有利特性。