Targeted Pharmacological Chaperones for Neurological Diseases

 描述(申请人提供)：这个小企业创新研究第一阶段项目旨在开发新的定向药理伴侣，能够调节活细胞和组织的高尔基体和内质网(ER)中的酶降解。如果成功，这项拟议的研究将提供必要的突破，以推动发现有前景的神经退行性疾病的新疗法和调节药物，这些疾病包括溶酶体储存疾病、阿尔茨海默病(AD)、肌萎缩侧索硬化症(ALS)、帕金森病(PD)、髓系白血病、胶质母细胞瘤、2型糖尿病、洛威综合征和相关退行性疾病以及涉及蛋白质错误折叠的医疗条件。在该项目的第一阶段，Marker基因技术公司将通过制备新的靶向药理伴侣，证明高尔基体和内质网中负荷和局部积累的改善，并证明与正常对照相比，在引起疾病的活细胞中提高溶酶体酶活性的有效性，从而确立这项技术的可行性。在第二阶段，这些和其他新的靶向药物结合物将在体外和体内进行评估，以确定它们是否能够影响活细胞中特定和局部的Tese酶的诱导，以及使用各种递送方法以细胞或组织特异性的方式缓解不需要的蛋白质降解或改善蛋白质的运输。这些新的药理伴侣和由此产生的靶向系统将提供调节高尔基体和内质网细胞器功能的创新方法，从而筛选二次给药或蛋白质给药的影响，影响蛋白质在细胞内的运输或分泌，使它们成为各种重要医学应用中的药物发现和基础研究的有用分析工具。我们的初步结果表明，所提出的方法有可能增加高谢病患者细胞系中药物伴侣的细胞内载量和靶向性，从而为临床治疗神经退行性疾病提供一种新的工具。

 DESCRIPTION (provided by applicant): This Small Business Innovation Research Phase I project aims to develop new targeted pharmacological chaperones capable of modulating enzyme degradation in the Golgi apparatus and Endoplasmic Reticulum (ER) of living cells and tissues. If successful, the proposed research will provide breakthroughs needed to advance the discovery of promising new therapies and modulating drugs for neurodegenerative disorders including lysosomal storage diseases, Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), myeloid leukemia, glioblastoma, Type 2 diabetes, Lowe syndrome and allied degenerative diseases and medical conditions involving protein misfolding. In Phase I of this project, Marker Gene Technologies, Inc. will establish the feasibility of the technology by preparing new targeted pharmacological chaperones, demonstrating improved loading and localized accumulation in the Golgi and ER and demonstrating efficacy for increasing lysosomal enzyme activity in living cells that are of disease origin in comparison to those from normal controls. In Phase II, these and additional new targeted drug conjugates will be evaluated in vitro and in vivo for their ability to affect specific and localized induction of tese enzymes in living cells as well as alleviate unwanted protein degradation or improve protein trafficking in a cell- or tissue- specific manner using a variety of delivery methods. These new pharmacological chaperones and the resulting targeting systems will provide innovative methods to modulate Golgi and ER organelle function and thereby screen for the influence of secondary drug or protein administration, affect intracellular trafficking of proteins or improve transport or secretion of proteins, making them useful analytical tools for drug discovery and basic research in a variety of significant medical applications. Our very preliminary results indicate the proposed methods have the potential to increase intracellular loading and targeting of pharmacological chaperones in human cell lines from patients with Gaucher disease, thereby providing a new tool to the arsenal of available therapeutics for clinical treatment of neurodegenerative disorders.