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

• 批准号: 8323729
• 负责人: KOSTANTIN DOBRENIS
• 金额: $ 36.44万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 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/8323729
• 关键词: 6 year old; Accounting; Adolescence; Affect; Allopregnanolone; Alzheimer' 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

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. PUBLIC HEALTH RELEVANCE: Lysosomal storage disorders are a group of about 60 rare, fatal genetic diseases caused by defects in a wide range of proteins associated with the endosomal-lysosomal system. Niemann-Pick type C (NPC) disease is a cholesterol-glycosphingolipid (GSL) storage disorder caused most commonly by defects in NPC1, a transmembrane protein believed critical in retroendocytic trafficking of substrates from lysosomes. Affected children typically appear normal at birth but exhibit progressive neurological decline beginning at 4-6 years of age with death often occurring in the second decade of life. Therapeutic options for NPC disease are very limited, with enzyme replacement, cell-mediated, and gene therapies providing little hope of benefit since the NPC1 protein is not soluble and secreted by cells. Such limitations have driven development of drugs that can limit the build-up of offending substrates in brain and other organs - known as substrate reduction therapy (SRT). We have pioneered the study of two such agents, N- butyldeoxynojirimycin (miglustat) and 2-hydroxypropyl ¿-cyclodextrin (HPBCD), both of which have shown efficacy for NPC disease in animal models. The purpose of this grant is to determine the mechanisms by which these two agents delay clinical disease and increase longevity in the murine model of NPC disease. This goal has now become all the more timely as a clinical trial involving HPBCD for treatment of children with NPC disease is being proposed to the FDA, to begin in 2012. Many of the individuals enrolling in this trial will also be under treatment with miglustat. Understanding the mechanisms of action and possible interactions (e.g., synergy) of HPBCD and miglustat are of paramount importance. Importantly, given similarities between NPC and other lysosomal diseases, as well as more common neurodegenerative conditions like Alzheimer's, successful treatments emerging here may provide benefit well beyond a single rare disease.

描述（由申请人提供）：尼曼-皮克 C 型 (NPC) 疾病是一种胆固醇-鞘糖脂 (GSL) 溶酶体贮积症，最常见的是由 NPC1 缺陷引起，NPC1 是一种跨膜蛋白，被认为对溶酶体底物的内吞后运输至关重要。儿童出生时表现正常，在早年发展为进行性神经系统疾病，并在二十岁时死亡。我们率先开发了两种治疗这种疾病的化合物。第一种是 N-丁基脱氧野尻霉素 (NB-DNJ) 或 miglustat 是已证实的 GSL 合成抑制剂，而第二种是羟丙基 ¿ -环糊精 (HPBCD) 是 FDA 批准的用于药物溶解的赋形剂，这两种化合物都能有效延迟 NPC1 疾病小鼠模型的神经疾病发作和延长寿命（分别延长 25% 和 100%）。对于 miglustat 的有效性，也缺乏对 Npc1 小鼠口服后神经节苷脂储存持续减少的证据。 HPBCD，虽然在 Npc1 小鼠中治疗后胆固醇和 GSL 储存都显着减少，但这种益处的机制完全未知，甚至关于其穿越血脑屏障的能力的争议实际上仍在继续。该提案将进行一系列补充。使用当前和新型试剂和动物模型进行体内和体外研究，以及定量高分辨率成像、生化和遗传评估，每个研究都针对鼻咽癌疾病的治疗机制，我们的前两个目标是精确定义 HPBCD 减少鼻咽癌的作用机制。我们的第三个目标是使用公正的基因分析方法来探索受胆固醇/GSL 储存在神经元中的影响的全方位代谢途径。利用在这些目标中吸取的经验教训，将在第四个目标中测试新的组合治疗策略，作为显着改善鼻咽癌儿童治疗的手段。 公众健康相关性：溶酶体贮积症是一组约 60 种罕见的致命性遗传疾病，由与内体-溶酶体系统相关的多种蛋白质缺陷引起，C 型尼曼-皮克 (NPC) 疾病是一种胆固醇-鞘糖脂疾病。 GSL）储存障碍最常由 NPC1 缺陷引起，NPC1 是一种跨膜蛋白，被认为对溶酶体底物的内吞后运输至关重要。受影响的儿童通常在出生时表现正常，但从 4-6 岁开始表现出进行性神经功能衰退，死亡通常发生在生命的第二个十年。鼻咽癌疾病的治疗选择非常有限，包括酶替代、细胞介导和基因治疗。由于 NPC1 蛋白不可溶且不能由细胞分泌，因此这种疗法几乎没有带来任何益处，因此人们开发出能够限制大脑和其他器官中有害底物积聚的药物，即所谓的底物减少疗法 (SRT)。我们开创了对两种此类药物 N-丁基脱氧野尻霉素（miglustat）和 2-羟丙基的研究 ¿ -环糊精（HPBCD），这两种药物均已在动物模型中显示出对鼻咽癌疾病的功效，这项资助的目的是确定这两种药物在鼻咽癌疾病小鼠模型中延缓临床疾病并延长寿命的机制。现在变得更加及时，因为 FDA 正在提议于 2012 年开始一项用于治疗患有 NPC 疾病的儿童的临床试验 HPBCD。许多参加该试验的个体也将接受了解 HPBCD 和 miglustat 的作用机制和可能的相互作用（例如协同作用）至关重要，鉴于 NPC 与其他溶酶体疾病以及阿尔茨海默病等更常见的神经退行性疾病之间的相似性，这里可能会出现成功的治疗方法。提供的益处远远超出单一罕见疾病。