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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病的细胞色素P450治疗空间项目摘要自从Tau被首次确定为神经系统缠结的关键成分以来的30年里，随后，神经变性的病原体-Tauopathy领域已经在以下方面取得了重要进展：了解异常形式的Tau蛋白如何导致损伤。Tau以复杂的方式与其他细胞成分和周围的细胞在大脑中。这种复杂性使得发展中的tau蛋白病治疗尤其具有挑战性。目前没有强烈改变疾病进展的疗法：已被批准的治疗方法，如胆碱酯酶抑制剂和NMDA受体拮抗剂美金刚，在早期至中期阿尔茨海默病患者中有适度的症状获益。新的努力包括减少Tau mRNA表达，减少胰岛素相关的代谢缺陷，解决异常Tau 在最近的临床试验中，靶向致病性Tau蛋白的传播，免疫疗法迄今为止，这些方法的功效有限，大脑的病理生理变化先于认知障碍数年甚至数十年，为治疗提供了一个广阔的时间窗口。工具包括PET、化学示踪剂和质量正在开发光谱测定法以原位检测前驱致病性Tau同种型。专注于孟德尔形式的tau蛋白病提供了更宽的治疗时间窗。一个有希望的方法是降低长期毒性的方法是靶向治疗，例如针对Tau蛋白本身。然而，Tau 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证明有限公司我们的实验室正在努力创造一种综合方法，既了解生物学， Tau病和开发新的先导化合物。关于后者，我们使用果蝇TauR 406 W 该平台作为一个整体的动物模型，以确定药物，可以减少Tau依赖性神经元损伤。一个尤其有希望的是FDA批准的药物阿那曲唑，一种细胞色素P450的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， TauR 406 W模型。值得注意的是，这种Tau拯救并不依赖于阿那曲唑对细胞凋亡的抑制。芳香化酶，表明阿那曲唑是通过脱靶活性起作用的，这表明改进的阿那曲唑类似物。我们建议使用我们新的苍蝇/化学平台来“进化”一种改进的阿那曲唑类似物（“anastrolog”），在整体环境中更好地解决Tau介导的损伤动物，同时保留至少一些阿那曲唑的有利性质。