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.

该建议研究两种致命的，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是由于酶酸的遗传缺陷引起的 鞘磷脂酶（ASM），导致鞘脂，鞘磷脂（SPM），细胞和 受影响患者的组织。相反，约95％的NPC患者在胆固醇转运中缺陷 蛋白质，NPC1，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重叠的缺陷，病理和临床表现。例如，约有50％的NPA/B 患者和所有NPC患者患有衰弱和威胁生命的中枢神经系统（CNS） 并发症，没有有效的疗法。为了满足这一重要的未满足的医疗需求 研究我们已经生成了一系列数据，支持了新型内源性大麻素（ECB）的使用 这些疾病的治疗。例如，我们发现酶脂肪酸酰胺的抑制剂 水解酶（FAAH）提升了几个ECB，在培养的神经元和组织中显着降低了SPM 型A/B NPD小鼠，导致CNS改善和延长寿命。我们还发现了一个重要的 从这些神经元表面的1型大麻素受体（CB1R）表达的下调 由于受体在溶酶体内部夹带，小鼠和来自NPA患者的脑组织中。这 FAAH抑制纠正异常。同样，用FAAH治疗NPC小鼠神经元 抑制剂导致SPM和胆固醇均减少，并且CB1R表达下调 在这些细胞的表面上。基于这些初步发现，我们提出了法庭 在NPA/B和NPC中，抑制可能是对中枢神经系统疾病的新型且高效的治疗方法 重新利用越过血脑屏障的现有FAAH抑制剂可能会迅速 可翻译为患者。追求这一目标并进一步了解这些疾病的相关性，三个 提出了具体目的：1）表征了分子机制（S）支撑的分子机制 NPA/B细胞和小鼠的FAAH抑制作用； 2）研究欧洲央行系统在NPC中的功能，并进一步研究 探索FAAH抑制作用，作为该疾病的潜在治疗方法，并且； 3）使用系统生物学和多运动 比较NPA/B和NPC影响的途径和网络的方法，并获得全局 FAAH抑制引起的分子变化的图片。我们也希望提供更多的见解 关于这些超罕见疾病与与之共享的常见神经系统疾病的相关性 重要的CNS病理学，包括阿尔茨海默氏病和帕金森氏病。