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

描述（由申请方提供）：C型尼曼-匹克（NPC）病是一种致死性复杂溶酶体贮积症，与进行性神经变性相关，主要由NPC 1突变引起，导致胆固醇和鞘脂蓄积。不幸的是，NPC疾病的治疗选择仍然非常有限。最近有报道称，组蛋白脱乙酰酶（HDAC）抑制剂可以纠正人NPC 1突变细胞中的胆固醇储存缺陷，为NPC疾病的新型治疗方案提供了潜在的基础。我们的实验室已经表明，鞘氨醇激酶2（SphK 2）在细胞核中产生的鞘脂代谢物鞘氨醇-1-磷酸是HDAC 1/2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，我们发现细胞核SphK 2也磷酸化FTY 720/芬戈莫德，一种批准用于治疗多发性硬化症的药物，其活性形式FTY 720-磷酸盐是一种有效的HDAC 1/2抑制剂，可上调胆固醇转运蛋白NPC 1和NPC 2。我们的目标是确定FTY 720的作用机制，并评估其在NPC 1突变细胞和NPC动物模型中的治疗潜力。在目标1中，我们将证明FTY 720通过抑制HDAC导致增加的NPC 1和NPC 2基因表达来纠正人NPC 1突变成纤维细胞中的胆固醇和鞘脂储存缺陷。在目标2中，我们的目标是确定向NPC 1突变小鼠施用FTY 720使胆固醇和鞘脂稳态正常化，改善肝功能，减少神经炎症和神经变性的严重程度，并抑制疾病进展。我们的长期目标是开发FTY 720作为NPC疾病治疗选择的潜在新基础。FTY 720作为NPC 1疾病患者的潜在治疗具有优于HDAC抑制剂的几个优点：其是口服生物可利用的药物; ii.其已经被批准用于治疗多发性硬化症的人类用途; iii.与其他HDAC抑制剂相比，其仅调节有限数量的基因（大多数与胆固醇和鞘脂代谢相关）的表达; iv.其具有良好的药代动力学和长的半衰期; v.其降低神经酰胺和鞘脂的水平; vi. 它的毒性低得多，并在大脑中积累，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治疗这种不治之症的新概念铺平道路。

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.