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：
9128332
负责人：
KOSTANTIN DOBRENIS
金额：
$ 9.57万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
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/9128332
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（由适用提供）：NIEMANN-PICK型C（NPC）疾病是一种胆固醇 - 糖磷脂脂（GSL）溶酶体储存障碍，通常是由NPC1缺陷引起的，NPC1的缺陷是一种跨膜蛋白，一种跨膜蛋白，一种在溶质膜中的近代蛋白质中被认为是关键的质体经常运输。大多数受影响的儿童在出生时看起来正常，早年就出现了进行性神经系统疾病，并在第二个十年中死亡。我们率先开发了这种疾病的两种化合物。首先是N-丁基氧基二霉素（NB-DNJ）或Miglustat是GSL合成的记录抑制剂，而第二，羟基丙烷€-Cyclodextrin（HPBCD）是ANFDA批准的用于药物溶液的ANFDA批准的。两种化合物在NPC1疾病的小鼠模型中延迟神经系统疾病的发作和延长寿命（分别为25％和100％）有效。然而，从负责其有效性的确切机制方面，两家药物都没有被理解。对于Miglustat，缺乏口服给NPC1小鼠口服后神经节苷脂储存量持续减少的证据。同样，对于HPBCD，虽然NPC1小鼠治疗后胆固醇和GSL的储存都大大降低，但这种益处的基础机制是完全未知的，实际上，争议甚至在其越过血脑屏障的能力上仍然存在。该建议将在体内和体外研究中进行一系列完整性，并采用当前和新型试剂和动物模型，以及定量的高分辨率成像，生化和遗传评估，每种都针对NPC疾病的治疗机制。我们的前两个目的是精确定义HPBCD在减少神经元中胆固醇/GSL储存方面的作用机制，并严格重新检查并评估Miglustat减少GSL合成作为其对神经元存活的有益影响的基础的能力。我们的第三个目标使用公正的基因分析方法来探索每种药物影响的全部代谢途径。利用这些目标中学到的经验教训，将在第四个目标中测试新的组合治疗策略，以此作为改善NPC疾病儿童治疗的一种手段。