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

描述（由申请人提供）：尼曼-皮克C型（NPC）病是一种致命的复杂溶酶体贮积症，与进行性神经退行性变相关，主要由NPC1突变导致胆固醇和鞘脂积累引起。不幸的是，鼻咽癌的治疗选择仍然非常有限。最近有报道称，组蛋白去乙酰化酶（HDAC）抑制剂可以纠正人NPC1突变细胞中的胆固醇储存缺陷，为鼻鼻癌疾病的新治疗选择提供了潜在的基础。我们的实验室已经证明鞘脂代谢产物鞘脂素-1-磷酸由鞘脂激酶2 （SphK2）在细胞核中产生，是一种内源性的HDAC1/2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也磷酸化FTY720/fingolimod（一种被批准用于治疗多发性硬化症的药物），并且其活性形式FTY720-phosphate是一种有效的HDAC1/2抑制剂，可上调胆固醇转运体NPC1和NPC2。我们的目标是确定FTY720的作用机制，并评估其在NPC1突变细胞和鼻咽癌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导致NPC1和NPC2基因表达增加来纠正人类NPC1突变成纤维细胞中的胆固醇和鞘脂储存缺陷。在Aim 2中，我们的目标是确定FTY720给药NPC1突变小鼠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退行性变的严重程度，并抑制疾病进展。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。与HDAC抑制剂相比，FTY720作为NPC1疾病患者的潜在治疗方法具有以下几个优势：1 .它是一种口服生物有效药物；2。它已经被批准用于治疗多发性硬化症；3。与其他HDAC抑制剂相比，它只调节有限数量基因的表达（大多数与胆固醇和鞘脂代谢有关）；Iv.药代动力学好，半衰期长；5 .降低神经酰胺和鞘脂的水平；6。

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.