Mechanisms of Substrate Reduction Therapy for Niemann-Pick C Disease

尼曼-匹克 C 病的底物还原治疗机制

基本信息

批准号：
8609077
负责人：
KOSTANTIN DOBRENIS
金额：
$ 34.72万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-01 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8609077
关键词：
6 year old Accounting Adolescence Affect Allopregnanolone Alzheimer&apos s Disease Animal Model Animals Behavioral Biochemical Biochemical Genetics Birth Blood - brain barrier anatomy Bone Marrow Stem Cell Transplantation Brain Brain Diseases Brain region Cells Cessation of life Child Cholesterol Clinical Clinical Trials Controlled Study Cyclodextrins Defect Development Disease Drug usage Effectiveness Enrollment Enzymes Evaluation Excipients Exhibits FDA approved Felis catus Functional disorder Gangliosides Gene Expression Profiling Genes Glycosphingolipids Goals Grant Hereditary Disease Human Image In Vitro Individual Integral Membrane Protein Intervention Intraventricular Injections Label Learning Life Link Longevity Lysosomes Mediating Membrane Metabolic Pathway Methods Miglustat Modeling Mus Nerve Degeneration Neurologic Neurons Oral Oral Administration Organ Pharmaceutical Preparations Proteins Publishing Purkinje Cells Rare Diseases Reagent Reporting Resolution Role Series Side Signal Transduction Subcutaneous Injections Supraoptic Vertical Ophthalmoplegia System Testing Therapeutic Time base cellular transduction combinatorial design drug development drug mechanism early childhood enzyme replacement therapy gene therapy improved in vitro Assay in vivo inhibitor/antagonist insight motor impairment mouse model nervous system disorder neurosteroids novel prevent successful intervention therapy resistant trafficking treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Niemann-Pick type C (NPC) disease is a cholesterol-glycosphingolipid (GSL) lysosomal storage disorder caused most commonly by defects in NPC1, a transmembrane protein believed critical in retroendocytic trafficking of substrates from lysosomes. Most affected children appear normal at birth, develop progressive neurological disease in their early years and die in their second decade. We have pioneered the development of two compounds for this disorder. The first, N-butyldeoxynojirimycin (NB-DNJ) or miglustat is a documented inhibitor of GSL synthesis, whereas the second, hydroxypropyl ¿-cyclodextrin (HPBCD), is an FDA-approved excipient used for drug solublization. Both compounds are efficacious in delaying onset of neurological disease and prolonging life (by 25% and 100%, respectively) in the mouse model of NPC1 disease. Yet neither drug is understood in terms of the precise mechanism responsible for its effectiveness. For miglustat, evidence for sustained reductions in ganglioside storage following oral administration to Npc1 mice is lacking. Similarly, for HPBCD, while both cholesterol and GSL storage are substantially reduced following treatment in Npc1 mice, the mechanism underlying this benefit is completely unknown, and indeed controversy continues even over its ability to cross the blood brain barrier. This proposal will carry out a series of complementary in vivo and in vitro studies employing current and novel reagents and animal models, and quantitative high-resolution imaging, biochemical and genetic evaluations, each directed at treatment mechanisms for NPC disease. Our first two aims are to precisely define HPBCD's mechanism of action in reducing cholesterol/GSL storage in neurons and to critically re-examine and assess miglustat's ability to reduce GSL synthesis as a basis for its beneficial impact on neuron survival. Our third aim uses an unbiased gene analysis approach to explore the full range of metabolic pathways impacted by each drug. Capitalizing on lessons learned in these aims, new combinatorial treatment strategies will be tested in the fourth aim as a means to substantially improve therapy for children with NPC disease.

描述（由申请人证明）：Niemannn-Pick型C（NPC）疾病是一种胆固醇 - 糖化脂蛋白（GSL）溶酶体储存障碍，通常是由于NPC1缺陷而引起的，这是一种跨膜蛋白，一种质感的近后蛋白质蛋白质，在腹膜内的近代蛋白质粘膜中的近代蛋白质出生时，出生时期的生产神经疾病在其第二个十年中死亡。羟基丙基 - 环糊精（HPBCD），是FDA申请的药物可溶性疾病的发病率。对于Miglustat，对于HPBCD而言，缺乏对NPC1小鼠的E储存的持续储存的证据提案将采用当前和新型试剂的体内和体外研究进行一系列互补的研究，并进行定量的高分辨率成像，生化和遗传评估，每个主管在治疗机制上的NPC疾病都必须精确定义HPBCD的疾病。 HPBCD的HPBCD在减少神经元中的胆固醇/GSL储存方面，重新检查并评估Miglustat减少GSL合成的能力，作为对神经元生存的有益影响。在第四个目标中被测试是为NPC疾病儿童的实质性改善。