Pharmacological Chaperone Therapy for the GM2 Gangliosidoses

 描述（由申请方提供）：GM 2神经节苷脂沉积症的药理学伴侣治疗。本申请的最终目标是用小分子药理学伴侣OT 1001治疗Tay-Sachs病（TSD）和Sandhoff病（SD），统称为GM 2神经节苷脂沉积症。药理学伴侣（PC）是选择性结合和稳定靶蛋白以促进正确折叠、减少过早降解和增加ER输出效率的小分子。这种方法广泛适用于增加特定蛋白质（突变体或野生型）的功能的疾病。 预计将提供治疗益处。OT 1001是一种有效的β-氨基己糖苷酶（这些疾病中的缺陷酶）靶向药理学伴侣，具有良好的生物利用度、血脑屏障穿透性、对β-氨基己糖苷酶的高选择性和低细胞毒性。当口服给药时，OT 1001处理使细胞中和野生型小鼠脑组织中的野生型和突变型β-氨基己糖苷酶活性水平增加高达3倍。具体地说，OrPhi Therapeutics将确定OT 1001对SD患者成纤维细胞系中β R505 Q突变型β-氨基己糖苷酶的效力。这将使我们能够确定当使用新的动物模型时需要实现的OT 1001的剂量范围，其中Hex B SD突变β R505 Q在β-Hex -/-背景上表达用于临床前给药研究。这种新创建的小鼠模型是唯一一种可以测试药理学伴侣的剂量和可能的功效的小鼠模型。此外，我们打算开发一种基于细胞的测定法，该测定法区分Hex A和Hex B的OT 1001应答性和非应答性变体，以确定哪些泰-萨二氏病和桑德霍夫病患者在未来的临床试验中将适合用OT 1001进行药理学伴侣治疗。GM 2神经节苷脂贮积症是威胁生命的神经退行性疾病，目前尚无治疗方法。这项工作的重点是提供临床前数据，以支持OT 1001通过IND使能研究和随后的GM 2神经节苷脂沉积症临床试验的开发。

 DESCRIPTION (provided by applicant): 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 the small molecule pharmacological chaperone, OT1001. 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. OT1001 is a potent ß-hexosaminidase (the deficient enzyme in these diseases) targeted pharmacological chaperone with good bioavailability, blood-brain barrier penetration, high selectivity for ß-hexosaminidase and low cytotoxicity. OT1001 treatment increases levels of wild-type and mutant ß-hexosaminidase activity up to 3-fold in cells and in wild-type mouse brain tissue when orally administered Specifically OrPhi Therapeutics will determine the potency of OT1001 for the ßR505Q mutant form of ß-hexosaminidase in a SD patient fibroblast cell line. This will allow us to determine the dose range of OT1001 that will need to be achieved when using a novel animal model in which the Hex B SD mutation ßR505Q is expressed on a ß-Hex -/- background for pre-clinical dosing studies. This newly created mouse model is the only mouse model in which a pharmacological chaperone can be tested for dosing and possibly efficacy. Additionally, we intend to develop a cell based assay that discriminates between OT1001 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 OT1001 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 OT1001 through IND enabling studies and subsequent clinical trials for the GM2 Gangliosidoses.