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21. 发明授权

US08092801B2 Prevention and treatment of synucleinopathic and amyloidogenic disease 有权
公开(公告)号：US08092801B2
公开(公告)日：2012-01-10
申请号：US12037081
申请日：2008-02-25
申请人： Dale B. Schenk , Eliezar Masliah , Manuel J. Buttini , Tamie J. Chilcote , Edward Rockenstein , Kate Dora Games
发明人： Dale B. Schenk , Eliezar Masliah , Manuel J. Buttini , Tamie J. Chilcote , Edward Rockenstein , Kate Dora Games
IPC分类号： A61K39/395
CPC分类号： C07K16/18 , A61K39/0007 , A61K2039/505 , A61K2039/55566 , A61K2039/6056 , C07K2317/34 , C07K2317/77 , C07K2317/80
摘要： The invention provides improved agents and methods for treatment of diseases associated with synucleinopathic diseases, including Lewy bodies of alpha-synuclein in the brain of a patient. Such methods entail administering agents that induce a beneficial immunogenic response against the Lewy body. The methods are particularly useful for prophylactic and therapeutic treatment of Parkinson's disease.

22. 发明申请

US20110223240A1 COMPOUNDS FOR REVERSING AND INHIBITING PROTEIN AGGREGATION, AND METHODS FOR MAKING AND USING THEM 有权
标题翻译：用于反转和抑制蛋白质聚集的化合物及其制备和使用它们的方法
公开(公告)号：US20110223240A1
公开(公告)日：2011-09-15
申请号：US13119400
申请日：2009-09-29
申请人： Eliezer Masliah , Brian Spencer , Edward Rockenstein , Robert Marr
发明人： Eliezer Masliah , Brian Spencer , Edward Rockenstein , Robert Marr
IPC分类号： A61K9/127 , C12N9/96 , A61K38/54 , A61P25/16 , A61P25/28 , A61P25/00 , C12N5/02 , B82Y5/00
CPC分类号： C07K14/4711 , A61K38/00 , C07K19/00
摘要： The invention provides compositions for increasing the clearance of protein aggregates, and pharmaceutical compositions comprising them, and methods for making and using them, including methods for accelerating protein aggregate clearance in the CNS, e.g., for treating diseases that are characterized by protein aggregation—including some degenerative neurological diseases such as Parkinson's disease. In one aspect, the compositions of the invention specifically target synuclein, beta-amyloid and/or tau protein aggregates, and the methods of the invention can be used to specifically prevent, reverse, slow or inhibit synuclein, beta-amyloid and/or tau protein aggregation. In alternative embodiments, the compositions and methods of the invention, are used to treat, prevent, reverse (partially or completely) or ameliorate (including slowing the progression of) degenerative neurological diseases related to or caused by protein aggregation, e.g., synuclein, beta-amyloid and/or tau protein aggregation. In one aspect, compositions and methods of this invention are used to treat, prevent or ameliorate (including slowing the progression of) Parkinson's disease, fronto-temporal dementia (FTD), Alzheimer's Disease (AD), Lewy body disease (LBD) and Multiple system atrophy (MSA).
摘要翻译：本发明提供了用于增加蛋白质聚集体清除率的组合物，以及包含它们的药物组合物，以及用于制备和使用它们的方法，包括用于加速CNS中的蛋白质聚集体清除的方法，例如用于治疗以蛋白质聚集为特征的疾病一些退行性神经系统疾病如帕金森病。在一个方面，本发明的组合物特异性靶向突触核蛋白，β-淀粉样蛋白和/或tau蛋白聚集体，并且本发明的方法可用于特异性地预防，逆转，减缓或抑制突触核蛋白，β-淀粉样蛋白和/或tau 蛋白质聚集。在替代实施方案中，本发明的组合物和方法用于治疗，预防，逆转（部分或完全）或改善（包括减缓进展）与蛋白质聚集相关或由其引起的退行性神经疾病，例如突触核蛋白，β - 淀粉样蛋白和/或tau蛋白聚集。一方面，本发明的组合物和方法用于治疗，预防或改善（包括减缓帕金森氏病，颞叶性痴呆（FTD），阿尔茨海默病（AD），路易体病（LBD）和多发性硬化症系统萎缩（MSA）。

23. 发明授权

US07795495B2 Transgenic mice for screening for inhibitors of protein aggregation and methods for making and using them 有权
标题翻译：用于筛选蛋白质聚集抑制剂的转基因小鼠及其制备和使用方法
公开(公告)号：US07795495B2
公开(公告)日：2010-09-14
申请号：US11675607
申请日：2007-02-15
申请人： Eliezer Masliah , Edward Rockenstein , Makoto Hashimoto
发明人： Eliezer Masliah , Edward Rockenstein , Makoto Hashimoto
IPC分类号： A01K67/027 , A01K67/00 , G01N33/00
CPC分类号： C12N15/8509 , A01K67/0275 , A01K67/0276 , A01K67/0278 , A01K2207/15 , A01K2217/00 , A01K2217/05 , A01K2217/075 , A01K2227/105 , A01K2267/0312 , A01K2267/0318 , A61K38/00 , A61K48/00 , C07K14/47 , C07K14/4711 , C12N2830/008
摘要： The methodologies of the present invention demonstrate that a critical balance between pro- and anti-amyloidogenic molecules exists that regulates amyloid formation and cell death in Alzheimer's disease and Parkinson's disease. β-Synuclein, the non-amyloidogenic homologue of α-synuclein, is a negative modulator of α-synuclein and Aβ aggregation, having neuroprotective properties against α-synuclein and Aβ neurotoxicity and that β-synuclein and therapeutic agents derived therefrom block amyloidogenesis and neurodegeneration in vivo. The method of the present invention establishes that β-synuclein blocks Aβ aggregation either by direct inhibition of Aβ amyloidogenesis or indirectly via either α-synuclein or its 35 a.a. NAC region, inferring neuroprotective characteristics within the effected cells. The generation of a transgenic mouse line and a cell system overexpressing α-synuclein characterizes the mechanisms by which β-synuclein blocks α-synuclein and Aβ aggregation and that this mechanism offers protection to the cell against amyloid formation as seen in the pathologies of Alzheimer's disease and Parkinson's disease.
摘要翻译：本发明的方法证明，存在调节淀粉样蛋白形成和阿尔茨海默病和帕金森病中的细胞死亡的促淀粉样变性分子和抗淀粉样蛋白形成分子之间的关键平衡。 α-突触核蛋白的非淀粉样变性同源物 - 突触核蛋白是α-突触核蛋白和A＆bgr的负调节剂; 聚集，对α-突触核蛋白和A＆bgr有神经保护作用; 神经毒性以及由此产生的结核分枝杆菌和其衍生的治疗剂在体内阻断淀粉样变性和神经变性。本发明的方法确定了结核分裂素A和bgr; 通过直接抑制A＆bgr的聚集; 淀粉样蛋白发生或间接通过α-突触核蛋白或其35 a.a. NAC区域，推断受影响细胞内的神经保护特征。转基因小鼠系的产生和过表达α-突触核蛋白的细胞系统的特征在于这样的机制，其中β-突触核蛋白阻断α-突触核蛋白和A＆bgr; 并且该机制为阿尔茨海默氏病和帕金森病的病理学中所观察到的针对淀粉样蛋白形成的细胞提供了保护。

24. 发明申请

US20100086545A1 Prevention and Treatment of Synucleinopathic and Amyloidogenic Disease 有权
标题翻译：预防和治疗突触核蛋白病和淀粉样变性疾病
公开(公告)号：US20100086545A1
公开(公告)日：2010-04-08
申请号：US12528439
申请日：2008-02-22
申请人： Dale B. Schenk , Eliezer Masliah , Manuel J. Buttini , Chilcote J. Tamie , Edward Rockenstein , Kate Dora Games
发明人： Dale B. Schenk , Eliezer Masliah , Manuel J. Buttini , Chilcote J. Tamie , Edward Rockenstein , Kate Dora Games
IPC分类号： A61K39/395 , C07K16/00 , C12P21/08 , C12N5/16 , A61P25/28
CPC分类号： C07K16/18 , A61K39/0007 , A61K2039/505 , A61K2039/55566 , C07K2317/21 , C07K2317/34 , C07K2317/92
摘要： The invention provides improved agents and methods for treatment of diseases associated with synucleinopathic diseases, including Lewy bodies of alpha-synuclein in the brain of a patient. Such methods entail administering agents that induce a beneficial immunogenic response against the Lewy body. The methods are particularly useful for prophylactic and therapeutic treatment of Parkinson's disease.
摘要翻译：本发明提供用于治疗与突触核蛋白病相关疾病（包括患者脑中的α-突触核蛋白的路易体）的改进剂和方法。这种方法需要对路易体诱导有益的免疫原性应答的给药剂。该方法对帕金森病的预防和治疗特别有用。

25. 发明授权

US07226746B1 Method for screening for anti-amyloidogenic properties and method for treatment of neurodegenerative disease 有权
标题翻译：筛选抗淀粉样变性的方法和治疗神经变性疾病的方法
公开(公告)号：US07226746B1
公开(公告)日：2007-06-05
申请号：US09806842
申请日：1999-10-06
申请人： Eliezer Masliah , Makoto Hashimoto , Edward Rockenstein
发明人： Eliezer Masliah , Makoto Hashimoto , Edward Rockenstein
IPC分类号： G01N33/53
CPC分类号： G01N33/5058 , G01N2333/47 , G01N2500/00
摘要： In methods for screening treatments for, and treatment of, neurodegenerative diseases, aggregation in neurons of NACP/α-synuclein is measured and expression of a non-amyloidogenic protein is stimulated in order to reduce the level aggregration. For purposes of screening agents for treatment of neurodegenerative disease, oxidative stress in the neuronal cells is stimulated by introducing a mixture of metal-ions and hydrogen peroxide. Examples of appropriate metals include iron, aluminum, and copper. After introduction of the agent under evaluation for stimulation of expression of non-amyloidogenic protein, the effectiveness is measured by testing for a decrease in the level of aggregation of NACP/α-synuclein. In an exemplary embodiment, the non-amyloidogenic protein is β-synuclein. The aggregation of NACP/α-synuclein is dependent upon the concentration of metal ions in the neuronal cells. In addition, the presence of chelating agents appears to modulate the build-up of NACP/α-synuclein aggregates which are responsible for synaptic and neuronal dysfunction.
摘要翻译：在用于筛选神经变性疾病的治疗和治疗方法中，测量NACP /α-突触核蛋白的神经元中的聚集，并刺激非淀粉样蛋白生成蛋白的表达以降低水平聚集。为了筛选用于治疗神经变性疾病的药剂，通过引入金属离子和过氧化氢的混合物刺激神经元细胞中的氧化应激。合适金属的实例包括铁，铝和铜。在引入用于刺激非淀粉样蛋白形成蛋白表达的试剂之后，通过测试NACP /α-突触核蛋白的聚集水平的降低来测量有效性。在一个示例性实施方案中，非淀粉样蛋白生成蛋白是β-突触核蛋白。 NACP /α-突触核蛋白的聚集取决于神经元细胞中金属离子的浓度。此外，螯合剂的存在似乎调节负责突触和神经元功能障碍的NACP /α-突触核蛋白聚集体的积聚。

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