Endocannabinoid-Based Treatment for the Neurologic Niemann-Pick Diseases

本提案研究两种致命的神经系统溶酶体贮积病，A/B型和C型尼曼-匹克病 疾病（分别为NPA/B和NPC）。NPA/B是由于遗传性缺乏酶酸 鞘磷脂酶（ASM），导致鞘脂、鞘磷脂（SPM）在细胞中积累， 受影响患者的组织。相反，约95%的NPC患者胆固醇转运存在缺陷， 蛋白质，NPC 1，导致胆固醇储存的主要缺陷。尽管它们的基因和蛋白质 NPA/B和NPC的病理和临床表现有重叠。例如，约50%的NPA/B 患者和所有患有NPC的患者遭受衰弱和危及生命的中枢神经系统（CNS）， 并发症，没有有效的治疗方法。为了解决这一重要的未满足的医疗需求，初步 我们的研究已经产生了一系列数据，支持使用一种新的内源性大麻素（ECB）为基础的 治疗这些疾病。例如，我们发现脂肪酸酰胺酶的抑制剂 水解酶（FAAH）可以升高几种ECB，但显着降低培养的神经元和组织中的SPM。 A/B型NPD小鼠，导致CNS改善和寿命延长。我们还发现了一个显著的 下调1型大麻素受体（CB 1 R）在这些神经元表面的表达， 小鼠和NPA患者的脑组织中，由于溶酶体内受体的截留。这 通过FAAH抑制纠正异常。类似地，用FAAH处理NPC小鼠神经元 抑制剂导致SPM和胆固醇降低，CB 1 R表达下调 在这些细胞的表面也是如此。基于这些初步研究结果，我们建议FAAH 抑制可能是NPA/B和NPC中CNS疾病的新型高效治疗， 并且重新利用现有的穿过血脑屏障的FAAH抑制剂可能会迅速 可以翻译给病人。为了实现这一目标，并进一步了解这些疾病的相关性，三个 提出了具体的目标：1）表征支撑保护作用的分子机制， 在NPA/B细胞和小鼠中的FAAH抑制; 2）研究ECB系统在NPC中的功能，并进一步 探索FAAH抑制作为这种疾病的潜在治疗方法; 3）使用系统生物学和多组学 比较NPA/B和NPC中受影响的途径和网络的方法，并获得全球 FAAH抑制引起的分子变化图。我们也希望提供进一步的见解 关于这些极其罕见的疾病与常见神经系统疾病的相关性， 显著的CNS病理学，包括阿尔茨海默病和帕金森病。

This proposal studies two fatal, neurological lysosomal storage diseases, Type A/B and Type C Niemann-Pick disease (NPA/B and NPC, respectively). NPA/B is due to an inherited deficiency of the enzyme acid sphingomyelinase (ASM), leading to the accumulation of the sphingolipid, sphingomyelin (SPM), in cells and tissues of affected patients. In contrast, ~95% of patients with NPC have a defect in the cholesterol transport protein, NPC1, leading to a primary defect in cholesterol storage. Despite their distinct genetic and protein defects, the pathological and clinical presentation of NPA/B and NPC overlap. For example, ~50% of NPA/B patients and all patients with NPC suffer from debilitating and life-threatening central nervous system (CNS) complications, and no effective therapies exist. To address this important unmet medical need, in preliminary studies we have generated a range of data supporting the use of a novel endocannabinoid (ECB)-based treatment for these disorders. For example, we have found that inhibitors of the enzyme fatty acid amide hydrolase (FAAH), which elevate several ECBs, significantly lowered SPM in cultured neurons and tissues of Type A/B NPD mice, leading to CNS improvements and extension of lifespan. We also found a significant down-regulation of the type-1 cannabinoid receptor (CB1R) expression on the surface of neurons from these mice and in brain tissue from a patient with NPA, due to entrapment of the receptor within the lysosome. This abnormality was corrected by FAAH inhibition. Similarly, treatment of NPC mouse neurons with FAAH inhibitors led to a reduction of both SPM and cholesterol, and there was a down-regulation of CB1R expression on the surface of these cells as well. Based on these preliminary findings, we propose that FAAH inhibition could be a novel and highly effective treatment for the CNS disease in both NPA/B and NPC, and that repurposing existing FAAH inhibitors that cross the blood brain barrier might be rapidly translatable to patients. To pursue this goal and further understand the relatedness of these disorders, three specific aims are proposed: 1) Characterize the molecular mechanism(s) underpinning the protective effects of FAAH inhibition in NPA/B cells and mice; 2) Investigate the function of the ECB system in NPC, and further explore FAAH inhibition as a potential treatment for this disease, and; 3) Use system biology and multi-omic approaches to compare the pathways and networks impacted in NPA/B and NPC, and to obtain a global picture of the molecular changes resulting from FAAH inhibition. We also hope to provide further insights regarding the relatedness of these ultra rare diseases to common neurologic diseases with which they share significant CNS pathology, including Alzheimer's and Parkinson's disease.