Endocannabinoid-Based Treatment for the Neurologic Niemann-Pick Diseases

基于内源性大麻素的神经尼曼匹克病治疗

• 批准号: 10701903
• 负责人: EDWARD H. SCHUCHMAN
• 金额: $ 52.28万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-09 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10701903
• 关键词: Address; Affect; Age; Agonist; Alzheimer' s Disease; Animal Model; Attenuated; B-Lymphocytes; Brain; CNR1 gene; Carrier Proteins; Cell model; Cell surface; Cells; Central Nervous System; Central Nervous System Diseases; Cholesterol; Cholesterol Homeostasis; Clinical; Computer Analysis; Crossbreeding; Data; Defect; Disease; Disease Progression; Down-Regulation; Endocannabinoids; Enzyme Inhibitor Drugs; Enzymes; Excision; FAAH inhibitor; Gene Expression; Genetic; Genomics; Goals; Hydrolysis; Inherited; Knockout Mice; Life; Ligands; Lipids; Longevity; Lysosomal Storage Diseases; Lysosomes; Medical; Metabolic Diseases; Molecular; Mus; NPC1 gene; Neimann-Pick' s Disease Type C; Nerve Degeneration; Neurodegenerative Disorders; Neurologic; Neurons; Niemann-Pick Diseases; Nuclear Pore Complex; Parkinson Disease; Pathologic; Pathology; Pathway interactions; Patients; Peroxisome Proliferator-Activated Receptors; Proteins; Proteomics; Rare Diseases; Role; Secondary to; Signal Transduction; Signaling Protein; Sphingolipids; Sphingomyelinase; Sphingomyelins; Surface; Systems Biology; Technology; Testing; Therapeutic Effect; Tissues; acid sphingomyelinase; anandamide; antagonist; blood-brain barrier crossing; brain tissue; cannabinoid receptor; effective therapy; endogenous cannabinoid system; enzyme deficiency; fatty acid amide hydrolase; gene expression database; improved; inhibitor; insight; lipidome; multiple omics; nervous system disorder; novel; novel therapeutic intervention; oleoylethanolamide; palmidrol; pharmacologic; protective effect; receptor; receptor expression; response; trafficking; transcription factor; transcriptome; treatment strategy

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.

该提案研究两种致命的神经性溶酶体贮积病，A/B 型和 C 型尼曼-皮克病 疾病（分别为 NPA/B 和 NPC）。 NPA/B 是由于酶酸的遗传性缺陷造成的 鞘磷脂酶 (ASM)，导致细胞内鞘脂、鞘磷脂 (SPM) 的积累， 受影响患者的组织。相比之下，约 95% 的鼻咽癌患者的胆固醇转运存在缺陷 NPC1 蛋白，导致胆固醇储存的主要缺陷。尽管它们具有独特的遗传和蛋白质 NPA/B 和 NPC 的缺陷、病理和临床表现有重叠。例如，约 50% 的 NPA/B 鼻咽癌患者和所有鼻咽癌患者都患有中枢神经系统 (CNS) 衰弱和危及生命的疾病 并发症，并且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 研究中，我们生成了一系列数据，支持使用基于新型内源性大麻素 (ECB) 的药物 这些疾病的治疗。例如，我们发现脂肪酸酰胺酶的抑制剂 水解酶（FAAH）可升高多种 ECB，显着降低培养的神经元和组织中的 SPM A/B 型 NPD 小鼠，可改善中枢神经系统并延长寿命。我们还发现了一个重要的 下调神经元表面 1 型大麻素受体 (CB1R) 的表达 小鼠和 NPA 患者的脑组织中，由于受体被困在溶酶体内。这 通过FAAH抑制纠正异常。同样，用 FAAH 处理 NPC 小鼠神经元 抑制剂导致 SPM 和胆固醇降低，并且 CB1R 表达下调 也在这些细胞的表面上。根据这些初步调查结果，我们建议 FAAH 抑制可能是治疗 NPA/B 和 NPC 中枢神经系统疾病的一种新型且高效的治疗方法， 重新利用现有的穿过血脑屏障的 FAAH 抑制剂可能会很快 可转化为患者。为了实现这一目标并进一步了解这些疾病的相关性，三个 提出了具体目标：1）表征支撑保护作用的分子机制 NPA/B 细胞和小鼠中的 FAAH 抑制； 2）研究ECB系统在NPC中的作用，并进一步 探索 FAAH 抑制作为该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 中受影响的路径和网络的方法，并获得全球 FAAH 抑制引起的分子变化图片。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其共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学，包括阿尔茨海默病和帕金森病。