权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

MODULATION OF CELLULAR CLEARANCE TO TREAT HUMAN DISEASE

调节细胞清除率来治疗人类疾病

基本信息

批准号：
8660354
负责人：
ANDREA BALLABIO
金额：
$ 33.89万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8660354
关键词：
Affect Alpha-glucosidase Aspartylglucosaminuria Autophagosome Biogenesis Biological Assay Brain Cardiac Cells Chemicals Child Childhood Data Disease Enzymes FDA approved Gene Delivery Gene Transfer Genes Genetic Glycogen Glycogen storage disease type II Goals In Vitro Inborn Genetic Diseases Infant Inherited Intramuscular Injections Laboratories Libraries Life Lysosomal Storage Diseases Lysosomes Mediating Metabolic Metabolism Methods Modeling Mus Muscle Muscle Fibers Myoblasts Myocardium Myopathy Neurodegenerative Disorders Nuclear Translocation Organ Organelles Patients Penetrance Pharmaceutical Preparations Pharmacological Treatment Phenotype Phosphorylation Preclinical Drug Evaluation Product Recycling Science Severities Simulate Skeletal Muscle Staging Symptoms Tamoxifen Testing Therapeutic Therapeutic Effect Time Tissues Toxic effect Transgenic Organisms Treatment Efficacy Viral Viral Vector base comparative efficacy disease phenotype enzyme replacement therapy gene replacement gene replacement therapy human disease in vivo kinase inhibitor mTOR Inhibitor macromolecule mouse model neurobehavioral novel therapeutics overexpression promoter screening transcription factor vector

项目摘要

DESCRIPTION (provided by applicant): The goal of this project is to generate proof-of-principle data on a completely novel therapeutic strategy that is based on the modulation of cellular clearance. This strategy will be tested on lysosomal storage diseases (LSDs), a group of over 50 inherited diseases with a progressive, multisystemic phenotype that mostly affects children. Currently available therapies for LSDs have major limitations. We have discovered a transcription factor, TFEB, that controls the biogenesis and function of lysosomes and autophagosomes (Sardiello et al. Science 2009; Settembre et al. Science, 2011) and we have shown that TFEB overexpression promotes cellular clearance of LSDs (Medina et al. Dev. Cell, 2011). Recently, we demonstrated that mTOR inhibitors promote TFEB nuclear translocation and activity (Settembre et al. EMBO J., 2012). In this project, we will: 1) test the therapeutic potential of inducible TFEB overexpression in a mouse model of Multiple Sulfatase Deficiency (MSD). The high severity and broad spectrum of the phenotype of this mouse model will enable us to test the effects of our therapeutic approach on multiple tissues; 2) test the therapeutic efficacy of AAV- mediated gene delivery of TFEB in a murine model of Pompe disease (PD), a disorder that primarily involves muscles and heart. This will allow us to compare the efficacy of a TFEB-based approach with more traditional enzyme replacement and gene replacement therapies. We have already obtained very encouraging preliminary data by viral-mediated TFEB overexpression in cultured myotubes derived from immortalized myoblasts and in vivo in a PD mouse model by intramuscular injection of AAV-TFEB; 3) identify chemical compounds that promote TFEB activity. We have developed a high-content screening assay based on TFEB nuclear translocation. Positive hits identified by high-content drug screening will be subject to a panel of in vitro secondary assays and promising compounds will be administered to mouse models of MSD and PD. If successful, the proposed approach will represent a paradigm shift in the treatment of LSDs. Contrary to existing therapies, which are directed towards single disease entities, our approach based on the modulation of cellular clearance, may have an impact on the therapy of many LSDs and of common, late onset neurodegenerative diseases.

描述（由申请人提供）：该项目的目标是产生基于细胞清除调节的全新治疗策略的原理证明数据。该策略将在溶酶体贮积病（lsd）上进行测试，lsd是一组超过50种遗传疾病，具有进行性，多系统表型，主要影响儿童。目前可用的lsd治疗方法有很大的局限性。我们已经发现了一种转录因子TFEB，它控制着溶酶体和自噬体的生物发生和功能（Sardiello et al.）。科学2009;settemre等人。Science, 2011)，我们已经证明TFEB过表达促进lsd的细胞清除（Medina等人）。Dev. Cell, 2011)。最近，我们证明mTOR抑制剂促进TFEB核易位和活性（Settembre等）。Embo j ., 2012)。在本项目中，我们将：1)在多发性硫酸酯酶缺乏症（MSD）小鼠模型中测试诱导性TFEB过表达的治疗潜力。这种小鼠模型的高严重性和广谱表型将使我们能够测试我们的治疗方法对多种组织的影响；2)在Pompe病（一种主要累及肌肉和心脏的疾病）小鼠模型中测试AAV介导的TFEB基因递送的治疗效果。这将使我们能够比较a