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1. 发明授权

US09464122B2 Methods and compositions comprising tau oligomers 有权
标题翻译：包含tau低聚物的方法和组合物
公开(公告)号：US09464122B2
公开(公告)日：2016-10-11
申请号：US13060143
申请日：2009-08-21
申请人： James G. Moe , Eliot J. Davidowitz
发明人： James G. Moe , Eliot J. Davidowitz
IPC分类号： C07K14/47 , A61K38/17 , G01N33/68
CPC分类号： C07K14/47 , A61K38/1709 , G01N2500/00 , G01N2800/2821
摘要： Tau protein has a causative role in Alzheimer's disease and multiple other neurodegenerative disorders exhibiting tau histopathology collectively termed tauopathies. The primary function of tau protein is to facilitate assembly and maintenance of microtubules in neuronal axons. In the disease process tau protein becomes modified, loses its affinity to microtubules and accumulates in the cell body where it forms aggregates. The large neurofibrillary tangles formed from tau protein assembled into filaments were thought to be the pathological structure of tau. However, more recent work indicates that smaller, soluble oligomeric forms of tau are best associated with neuron loss and memory impairment. Here, novel compositions of tau oligomers and novel mechanisms for tau oligomer nucleation, extension and termination are taught. Methods for producing and purifying these structures for the development of small molecule and immunotherapeutics as well as antibodies for biomarkers of neurodegenerative diseases are taught.
摘要翻译： Tau蛋白在阿尔茨海默病和多种其他神经退行性疾病中起着重要的作用，其表现为组织病理学统称为tau蛋白病。 tau蛋白的主要功能是促进神经元轴突中微管的组装和维持。在疾病过程中，tau蛋白被修饰，丧失其对微管的亲和力，并在细胞体积聚，形成聚集体。由tau蛋白形成的大的神经原纤维缠结组织成长丝被认为是tau的病理结构。然而，最近的工作表明，较小的可溶性寡聚体形式的tau最好与神经元损失和记忆障碍有关。在这里，教导了tau寡聚体的新型组合物和用于tau低聚物成核，延伸和终止的新机制。制备和纯化用于开发小分子和免疫治疗剂的这些结构的方法以及用于神经变性疾病的生物标志物的抗体。

2. 发明申请

US20110312059A1 TAU PROTEASE COMPOSITIONS AND METHODS 审中-公开
标题翻译： TAU PROTEASE组合物和方法
公开(公告)号：US20110312059A1
公开(公告)日：2011-12-22
申请号：US13060196
申请日：2009-08-20
申请人： James G. Moe , Eliot J. Davidowitz
发明人： James G. Moe , Eliot J. Davidowitz
IPC分类号： C12N9/64 , C07K2/00 , C07K19/00
CPC分类号： C07K14/47 , A61K38/1709 , C12N9/6421
摘要： Tau protein has a causative role in Alzheimer's disease and multiple other neurodegenerative disorders exhibiting tau histopathology collectively termed tauopathies. The primary function of tau protein is to facilitate assembly and maintenance of microtubules in neuronal axons. In the disease process tau protein becomes modified, loses its affinity to microtubules and accumulates in the cell body where it forms aggregates. The large neurofibrillary tangles formed from tau protein assembled into filaments were thought to be the pathological structure of tau. However, more recent work indicates that smaller, soluble oligomeric forms of tau are best associated with neuron loss and memory impairment. A novel and unexpected protease activity has been discovered to be associated with tau in oligomeric but not monomeric structures. Methods have been developed to form and purify tau protease and to assay its activity. Tau protease activity constitutes a totally novel mechanism for tau-mediated neurodegenerative disease by causing tau loss of function, as it cleaves itself, and gain of toxic function as it can cleave other proteins and facilitate cell death through apoptotic and/or senescence pathways. Tau protease presents a novel and unique target for the development of therapeutics that may be achieved by several strategies including by inhibiting the tau oligomer enzymatic activity.
摘要翻译： Tau蛋白在阿尔茨海默病和多种其他神经退行性疾病中起着重要的作用，其表现为组织病理学统称为tau蛋白病。 tau蛋白的主要功能是促进神经元轴突中微管的组装和维持。在疾病过程中，tau蛋白被修饰，丧失其对微管的亲和力，并在细胞体积聚，形成聚集体。由tau蛋白形成的大的神经原纤维缠结组织成长丝被认为是tau的病理结构。然而，最近的工作表明，较小的可溶性寡聚体形式的tau最好与神经元损失和记忆障碍有关。已经发现一种新颖且意想不到的蛋白酶活性与寡聚而不是单体结构中的tau相关。已经开发了形成和纯化tau蛋白酶并测定其活性的方法。 Tau蛋白酶活性构成了tau介导的神经退行性疾病的全新机制，通过引起功能丧失，因为它自身断裂，获得毒性功能，因为它可以切割其他蛋白质，并通过凋亡和/或衰老途径促进细胞死亡。 Tau蛋白酶提供了一种新颖而独特的治疗开发目标，可通过几种策略实现，包括通过抑制tau低聚酶酶活性。

3. 发明授权

US09506051B2 Tau protease compositions and methods of use 有权
标题翻译： Tau蛋白酶组合物和使用方法
公开(公告)号：US09506051B2
公开(公告)日：2016-11-29
申请号：US14119154
申请日：2012-05-18
申请人： James G. Moe , Eliot J. Davidowitz , Patricia Lopez
发明人： James G. Moe , Eliot J. Davidowitz , Patricia Lopez
IPC分类号： C12N9/64 , C12Q1/37 , G01N33/68 , A61K38/00 , A61K38/48 , A61K39/395 , C07K16/40 , G01N33/573
CPC分类号： C12N9/6424 , A61K38/00 , A61K38/482 , A61K39/3955 , C07K16/40 , C12Q1/37 , G01N33/573 , G01N33/6896 , G01N2800/2821
摘要： Disclosed are mammalian tau proteases, as well as proteolytically-active fragments, variants, and mutants thereof. Also disclosed are polynucleotides and recombinant expression vectors that encode these polypeptides, as well as methods for producing such proteins in selected recombinant host cells, and for using the compositions in a variety of diagnostic and analytical assays.
摘要翻译：公开了哺乳动物tau蛋白酶，以及蛋白水解活性片段，变体和突变体。还公开了编码这些多肽的多核苷酸和重组表达载体，以及在选择的重组宿主细胞中产生此类蛋白质的方法，以及在各种诊断和分析测定中使用该组合物。

4. 发明申请

US20120029169A1 METHODS AND COMPOSITIONS COMPRISING TAU OLIGOMERS 有权
标题翻译：包含TAU OLIGOMERS的方法和组合物
公开(公告)号：US20120029169A1
公开(公告)日：2012-02-02
申请号：US13060143
申请日：2009-08-21
申请人： James G. Moe , Eliot J. Davidowitz
发明人： James G. Moe , Eliot J. Davidowitz
IPC分类号： C07K14/435
CPC分类号： C07K14/47 , A61K38/1709 , G01N2500/00 , G01N2800/2821
摘要： Tau protein has a causative role in Alzheimer's disease and multiple other neurodegenerative disorders exhibiting tau histopathology collectively termed tauopathies. The primary function of tau protein is to facilitate assembly and maintenance of microtubules in neuronal axons. In the disease process tau protein becomes modified, loses its affinity to microtubules and accumulates in the cell body where it forms aggregates. The large neurofibrillary tangles formed from tau protein assembled into filaments were thought to be the pathological structure of tau. However, more recent work indicates that smaller, soluble oligomeric forms of tau are best associated with neuron loss and memory impairment. Here, novel compositions of tau oligomers and novel mechanisms for tau oligomer nucleation, extension and termination are taught. Methods for producing and purifying these structures for the development of small molecule and immunotherapeutics as well as antibodies for biomarkers of neurodegenerative diseases are taught.
摘要翻译： Tau蛋白在阿尔茨海默病和多种其他神经退行性疾病中起着重要的作用，其表现为组织病理学统称为tau蛋白病。 tau蛋白的主要功能是促进神经元轴突中微管的组装和维持。在疾病过程中，tau蛋白被修饰，丧失其对微管的亲和力，并在细胞体积聚，形成聚集体。由tau蛋白形成的大的神经原纤维缠结组织成长丝被认为是tau的病理结构。然而，最近的工作表明，较小的可溶性寡聚体形式的tau最好与神经元损失和记忆障碍有关。在这里，教导了tau寡聚体的新型组合物和用于tau低聚物成核，延伸和终止的新机制。制备和纯化用于开发小分子和免疫治疗剂的这些结构的方法以及用于神经变性疾病的生物标志物的抗体。

5. 发明申请

US20080220449A1 Biomarkers and assays for Alzheimer's disease 审中-公开
标题翻译：阿尔茨海默病的生物标记物和测定法
公开(公告)号：US20080220449A1
公开(公告)日：2008-09-11
申请号：US12069399
申请日：2008-02-08
申请人： Sara Vasan , Eliot J. Davidowitz , James G. Moe
发明人： Sara Vasan , Eliot J. Davidowitz , James G. Moe
IPC分类号： G01N33/53 , G01N33/00 , C07K16/18 , G01N33/566
CPC分类号： C07K16/18 , G01N33/6896 , G01N2800/2821 , G01N2800/56
摘要： Methods, compositions and systems are provided for diagnosing, stratifying, or monitoring the progression or regression of Alzheimer's disease (AD), the methods, compositions and systems comprise detecting in a sample a level of at least one AD biomarker, the AD biomarker comprising at least phosphorylated tau pT217, soluble tau oligomer, tau-amyloid-beta 1-42 complex, a fragment thereof or a combination thereof and comparing the level from the sample to a reference level of phosphorylated tau pT217, soluble tau oligomer, and/or tau-amyloid-beta 1-42 complex to diagnose or stratify or monitor the progression or regression of AD. In various embodiments, diagnostic assay and screening kits are provided. In various embodiments, the assay and kits provided can monitor the therapeutic effect of a drug and/or AD treatment. In various embodiments, the assay can be used to screen for drugs that disrupt the AD biomarker(s)
摘要翻译：提供了用于诊断，分层或监测阿尔茨海默病（AD）的进展或消退的方法，组合物和系统，所述方法，组合物和系统包括在样品中检测至少一种AD生物标志物的水平，所述AD生物标志物包含最小磷酸化tau pT217，可溶性tau低聚物，tau-淀粉样蛋白-β1-42复合物，其片段或其组合，并将来自样品的水平与磷酸化tau pT217，可溶性tau低聚物和/或tau的参考水平进行比较 - 淀粉样蛋白-β1-42复合物来诊断或分层或监测AD的进展或消退。在各种实施方案中，提供诊断测定和筛选试剂盒。在各种实施方案中，提供的测定和试剂盒可以监测药物和/或AD治疗的治疗效果。在各种实施方案中，该测定可用于筛选破坏AD生物标志物的药物，

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