Pharmacological Chaperone Therapy for the GM2 Gangliosidoses

项目总结/摘要 GM 2神经节苷脂代谢障碍的药物伴侣治疗 这项应用的最终目标是治疗泰-萨二氏病（TSD）和山德霍夫病（Sandhoff） 疾病（SD）统称为GM 2神经节苷脂沉积症，具有小分子药理学 监护人药理学分子伴侣（PC）是选择性结合并 稳定靶蛋白以促进正确折叠，减少过早降解并增加 出口效率。这种方法广泛适用于增加免疫力的疾病。 预测特定蛋白质（突变体或野生型）的功能提供治疗益处。 OT 1009是一种有效的β-氨基己糖苷酶（这些疾病中的缺陷酶），靶向 具有良好的生物利用度、血脑屏障穿透性、高生物利用度和高生物利用度的药理学伴侣 对β-氨基己糖苷酶的选择性和低细胞毒性。OT 1009处理增加了野生型 型和突变型β-氨基己糖苷酶在细胞中的活性高达4倍。OrPhi Therapeutics 开发了唯一的小鼠模型（β R484 Q/β R484 Q），其中药理学伴侣蛋白 可以测试治疗的剂量和功效。我们打算用这个模型来测试我们的 药理学伴侣OT 1009在长期给药和功效研究中的应用。另外我们 本发明旨在开发一种基于细胞测定，其区分OT 1009应答性和非应答性 Hex A和Hex B的应答变体，以确定哪些泰-萨二氏病和桑德霍夫病 在未来的临床试验中，患者将接受OT 1009的药理学伴侣治疗。 审判GM 2神经节苷脂沉积症是威胁生命的神经退行性疾病， 治疗目前可用。这项工作的重点是提供临床前数据，以支持 通过IND使能研究和随后的临床试验开发OT 1009， GM 2神经节苷脂沉积症。

Project Summary/Abstract Pharmacological Chaperone Therapy for the GM2Gangliosidoses The ultimate goal of this application is the treatment of Tay-Sachs Disease (TSD) and Sandhoff Disease (SD) collectively called the GM2 Gangliosidoses with a small molecule pharmacological chaperone. Pharmacological chaperones (PCs) are small molecules that selectively bind and stabilize target proteins to facilitate proper folding, reduce premature degradation and increase the efficiency of ER export. This approach is broadly applicable to diseases where increasing the function of a specific protein (mutant or wild-type) is predicted to provide therapeutic benefit. OT1009 is a potent β-hexosaminidase (the deficient enzyme in these diseases) targeted pharmacological chaperone with good bioavailability, blood-brain barrier penetration, high selectivity for β-hexosaminidase and low cytotoxicity. OT1009 treatment increases levels of wild- type and mutant β-hexosaminidase activity up to 4-fold in cells. OrPhi Therapeutics has developed the only mouse model (βR484Q/βR484Q) in which a pharmacological chaperone therapy can be tested for dosing and efficacy. We intend to use this model to test our pharmacological chaperone OT1009 in long term dosing and efficacy studies. Additionally, we intend to develop a cell based assay that discriminates between OT1009 responsive and non- responsive variants of Hex A and Hex B to determine which Tay-Sachs and Sandhoff Disease patients will be amenable to pharmacological chaperone therapy with OT1009 in future clinical trials. The GM2 Gangliosidoses are life threatening neurodegenerative diseases for which no treatment is currently available. The focus of this work is to provide pre-clinical data to support the development of OT1009 through IND enabling studies and subsequent clinical trials for the GM2 Gangliosidoses.