Endocannabinoid-Based Treatment for the Neurologic Niemann-Pick Diseases

这项建议研究了两种致命的神经系统溶酶体储存疾病，A/B型和C型Niemann-Pick 疾病(分别为NPA/B和NPC)。NPA/B是由于遗传性的酵母酸缺乏所致 鞘磷脂酶(ASM)，导致神经鞘磷脂(SPM)在细胞和 受影响患者的组织。相比之下，~95%的鼻咽癌患者在胆固醇运输方面存在缺陷 蛋白质，NPC1，导致胆固醇储存的主要缺陷。尽管它们有不同的基因和蛋白质 NPA/B和NPC的缺陷、病理和临床表现重叠。例如，约50%的NPA/B 鼻咽癌患者和所有患者都患有衰弱和危及生命的中枢神经系统(CNS)。 并发症，而且没有有效的治疗方法。为了解决这一重要的未得到满足的医疗需求，在初步 我们已经产生了一系列数据支持使用一种新型的内源性大麻素(ECB) 对这些疾病的治疗。例如，我们发现脂肪酸酰胺酶的抑制剂 升高几种ECB的水解酶(FAAH)显著降低培养神经元和组织中的SPM。 A/B型NPD小鼠，改善中枢神经系统，延长寿命。我们还发现了一个重要的 这些药物下调神经元表面1型大麻素受体(CB1R)的表达 小鼠和一名NPA患者的脑组织中，这是由于受体被困在溶酶体中。这 异常通过FAAH抑制得到纠正。同样，FAAH对鼻咽癌小鼠神经元的处理作用 抑制剂导致SPM和胆固醇的减少，CB1R的表达下调 在这些细胞的表面也是如此。基于这些初步发现，我们建议FAAH 抑制可能是治疗NPA/B和鼻咽癌中枢神经系统疾病的一种新的高效方法， 改变现有的FAAH抑制剂穿过血脑屏障的用途可能会迅速 可翻译给患者。为了追求这一目标并进一步了解这些疾病的相关性，有三个 提出的具体目标是：1)表征支持保护作用的分子机制(S) FAAH在NPA/B细胞和小鼠中的抑制作用；2)研究ECB系统在NPC中的功能，并进一步 探索抑制FAAH作为一种潜在的治疗方法；以及3)使用系统生物学和多组学 比较受NPA/B和NPC影响的路径和网络的方法，并获得全球 FAAH抑制引起的分子变化的图片。我们也希望提供进一步的见解 关于这些超罕见疾病与它们共同患有的常见神经系统疾病的相关性 重要的中枢神经系统病理，包括阿尔茨海默氏症和帕金森氏病。

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.