Discovery and evaluation of novel therapy for Niemann-Pick type C targeting NPC1

针对 NPC1 的 Niemann-Pick C 型新疗法的发现和评估

基本信息

批准号：
8814287
负责人：
SARAH SPIEGEL
金额：
$ 19.06万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8814287
关键词：
Animal Model Brain Brain Diseases Cell Nucleus Cells Ceramides Cholesterol Clinical Complex Defect Development Disease Disease Progression Down-Regulation Drug Kinetics Esterification Evaluation FDA approved Fibroblasts Gene Expression Gene Expression Profile Gene Expression Regulation Genes Goals HDAC1 gene Half-Life Health Histone Deacetylase Inhibitor Histones Homeostasis Human Immunosuppressive Agents Life Support Care Link Lipids Lymphocyte Mass Spectrum Analysis Mediating Mediator of activation protein Memory impairment Metabolic Metabolism Methods Modeling Molecular Multiple Sclerosis Mus Mutant Strains Mice Mutation Nerve Degeneration Neurodegenerative Disorders Neurologic Neurons Nuclear Organelles Patients Pharmaceutical Preparations Play Prodrugs Proteins Proteolytic Processing Psychiatry Reporting Severities Sphingolipids Sphingosine Supraoptic Vertical Ophthalmoplegia Testing Therapeutic Transferase Work analog base cholesterol trafficking cholesterol transporters effective therapy epigenetic regulation human disease improved inhibitor/antagonist inorganic phosphate liver function lymph nodes mutant nervous system disorder neuroinflammation novel prevent progressive neurodegeneration sensor sphingosine 1-phosphate sphingosine kinase

项目摘要

DESCRIPTION (provided by applicant): Niemann-Pick type C (NPC) disease is a fatal complex lysosomal storage disorder associated with progressive neurodegeneration predominately caused by mutations in NPC1 resulting in accumulation of cholesterol and sphingolipids. Unfortunately, treatment options for NPC disease are still very limited. It was recently reported that histone deacetylase (HDAC) inhibitors can correct cholesterol storage defects in human NPC1 mutant cells, providing a potential basis for novel treatment options for NPC disease. Our lab has shown that the sphingolipid metabolite sphingosine-1-phosphate produced in the nucleus by sphingosine kinase 2 (SphK2) is an endogenous inhibitor of HDAC1/2, linking sphingolipid metabolism to gene expression. In preliminary studies, we found that nuclear SphK2 also phosphorylates FTY720/fingolimod, a drug approved for treatment of multiple sclerosis, and that its active form, FTY720-phosphate, is a potent HDAC1/2 inhibitor that upregulates the cholesterol transporters NPC1 and NPC2. Our objectives are to determine the mechanisms of action of FTY720 and evaluate its therapeutic potential in NPC1 mutant cells and in animal models of NPC. In Aim 1, we will demonstrate that FTY720 corrects cholesterol and sphingolipid storage defects in human NPC1 mutant fibroblasts by inhibition of HDACs leading to increased NPC1 and NPC2 gene expression. In Aim 2, our objective is to establish that administration of FTY720 to NPC1 mutant mice normalizes cholesterol and sphingolipid homeostasis, improves liver function, reduces neuroinflammation, and severity of neurodegeneration, and suppresses disease progression. Our long-term goal is to develop FTY720 as a potential new basis for treatment options for NPC disease. FTY720 has several advantages over HDAC inhibitors as potential treatment for NPC1 disease patients: i. it is an orally bio-available drug; ii. it has already been approved for human use for the treatment of multiple sclerosis; iii. it regulates expression of only a limited number of genes (a majority related to cholesterol and sphingolipid metabolism) compared to other HDAC inhibitors; iv. it has good pharmacokinetics and a long half life; v. it reduces levels of ceramide and sphingolipids; vi. it is much less toxic and accumulates in the brain and would hence be able to treat the neurological sequelae of NPC. We hope our studies will pave the way to explore this new concept for treatment of this incurable disease.

描述（由申请人提供）：Niemann-Pick型C（NPC）疾病是一种致命的复杂溶酶体储存障碍，与进行性神经退行性疾病有关，主要由NPC1突变引起，导致胆固醇和鞘脂的积累。不幸的是，NPC疾病的治疗选择仍然非常有限。最近有报道说，组蛋白脱乙酰基酶（HDAC）抑制剂可以纠正人NPC1突变细胞中的胆固醇储存缺陷，从而为NPC疾病的新型治疗方案提供了潜在的基础。我们的实验室表明，由鞘氨醇激酶2（SPHK2）在细胞核中产生的鞘脂代谢物鞘氨酸1-磷酸（SPHK2）是HDAC1/2的内源性抑制剂，将鞘脂代谢与基因表达联系起来。在初步研究中，我们发现核SPHK2还磷酸化FTY720/fingolimod，一种批准用于治疗多发性硬化症的药物，其活性形式为FTY720-磷酸盐，是一种有效的HDAC1/2抑制剂，可上调胆固醇转运蛋白转运蛋白NPC1和NPC2。我们的目标是确定FTY720的作用机理，并评估其在NPC1突变细胞和NPC动物模型中的治疗潜力。在AIM 1中，我们将证明FTY720通过抑制HDAC来纠正人NPC1突变体成纤维细胞中的胆固醇和鞘脂储存缺陷，从而导致NPC1和NPC2基因表达增加。在AIM 2中，我们的目标是确定FTY720对NPC1突变体小鼠的施用使胆固醇和鞘脂稳态归一化，改善了肝功能，降低了神经炎症以及神经变性的严重程度，并抑制了疾病的进展。我们的长期目标是开发FTY720作为NPC疾病治疗选择的潜在新基础。 FTY720比HDAC抑制剂具有多个优势，作为NPC1疾病患者的潜在治疗方法：i。这是一种口服生物利用的药物； ii。它已经被批准用于治疗多发性硬化症的人类使用。 iii。与其他HDAC抑制剂相比，它仅调节有限数量的基因（与胆固醇和鞘脂代谢有关的多数）的表达； iv。它具有良好的药代动力学和长寿。 v。它降低了神经酰胺和鞘脂的水平； vi。它的毒性要小得多，并且在大脑中积聚，因此能够治疗NPC的神经后遗症。我们希望我们的研究将为探索这种无法治愈的疾病的新概念铺平道路。