Pharmacological Chaperone Therapy for the GM2 Gangliosidoses

GM2 神经节苷脂病的药理学伴侣治疗

• 批准号: 9409876
• 负责人: Eric Sjoberg
• 金额: $ 86.02万
• 依托单位: ORPHI THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9409876
• 关键词: Affect; Age-Months; Alleles; Alpha Cell; Award; Binding; Biochemical; Biological Assay; Biological Availability; Blood - brain barrier anatomy; Cells; Clinical Data; Clinical Trials; Databases; Development; Disease; Disease model; Dose; Drug Kinetics; Enzymes; Foundations; Future; Gangliosides; Gangliosidoses GM2; Glycoconjugates; Goals; Grant; Half-Life; Hereditary Disease; Human; Kinetics; Knock-in Mouse; Lead; Life; Measurable; Modeling; Molecular Chaperones; Mus; Mutation; Neuraxis; Neurodegenerative Disorders; Patients; Penetration; Pharmaceutical Preparations; Pharmacology; Phase; Prevention therapy; Property; Proteins; Rare Diseases; Recruitment Activity; Regimen; Research; Sandhoff Disease; Small Business Innovation Research Grant; Tay-Sachs Disease; Testing; Therapeutic; Therapeutic Uses; Time; Variant; Work; analog; base; beta-n-acetylhexosaminidase; cytotoxicity; design; disease-causing mutation; drug candidate; effective therapy; efficacy study; enzyme deficiency; improved; in vivo; mouse model; mutant; pre-clinical; premature; small molecule

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.

项目摘要/摘要 GM2神经节苷脂增多症的药物伴侣治疗 这个应用程序的最终目标是治疗泰-萨克斯病(TSD)和桑德霍夫 本病(SD)统称为GM2神经节苷脂具有小分子药理作用 监护人。药理伴侣(PC)是一种小分子，选择性地结合和 稳定靶蛋白，促进正确折叠，减少过早降解，增加 ER出口的效率。这种方法广泛适用于疾病，其中增加 一种特定蛋白质(突变型或野生型)的功能被预测为提供治疗益处。 OT1009是一种有效的β-己糖苷酶(这些疾病中的缺陷酶) 药理伴侣具有良好的生物利用度，血脑屏障穿透能力强， 对β-氨基己糖苷酶的选择性和低细胞毒性。OT1009治疗增加了野生- 类型和突变型β-己糖苷酶活性在细胞中高达4倍。OrPhi治疗公司已经 开发了唯一的小鼠模型(βR484Q/βR484Q)，在该模型中，药理伴侣 治疗可以通过剂量和疗效进行测试。我们打算用这个模型来测试我们的 药理伴侣OT1009长期给药和疗效研究。此外，我们 打算开发一种基于细胞的检测方法，区分OT1009反应和无反应 Hex A和Hex B的反应性变异以确定哪种Tay-Sachs和Sandhoff病 在未来的临床中，患者将接受OT1009的药物伴侣治疗 审判。GM2神经节苷脂增多症是一种危及生命的神经退行性疾病 治疗目前是可用的。这项工作的重点是为临床前数据提供支持 通过IND使能研究和随后的临床试验开发OT1009 GM2冈廖西德斯。