Therapeutic Targets for Niemann-Pick Type C Neurodegeneration

摘要 C型尼曼-匹克病（NPC）是一种常致命的常染色体隐性遗传性脂质储存疾病， 年龄患者出现临床异质性表型，包括严重的，进行性的 神经变性，肝肿大，和早期死亡。NPC通常是由以下基因的功能缺失突变引起的： NPC 1基因（95%的病例），编码输出所需的多通道跨膜糖蛋白 来自晚期内体和溶酶体的未酯化胆固醇。尽管我们逐渐认识到 NPC 1在细胞内胆固醇运输中的作用，NPC的诊断仍然特别暗淡。目前有 没有FDA批准的疾病修饰疗法，患者通常在儿童期死亡，这反映了 我们目前对疾病发病机理的认识和显著未满足的医疗需求。我们的长期目标是 为NPC患者的疾病改善疗法的发展做出贡献。下一步是实现 这一目标是实现本申请的总体目标：确定中枢神经系统疾病的关键靶点 这是可以通过药物开发工作来利用的发病机制。我们的中心假设是NPC 1缺陷 引起神经元和少突胶质细胞的毒性，这是NPC神经病理学的基础。而且我们 假设这种毒性可以通过旨在减少细胞内 脂质储存是疾病的特征或通过纠正突变NPC 1蛋白的错误折叠。这些 概念是基于强大的初步数据支持我们的模型NPC发病机制和使用 创新的治疗方法来挽救疾病表型。我们会用遗传学，生物化学，组织学， 和表型分析，以：建立神经元脂质储存和毒性被拯救的程度， 优化的合成HDL纳米颗粒（目标1）;确定少突胶质细胞谱系细胞在NPC中的作用 神经病理学（目的2）;并建立蛋白质稳态调节剂在人源化NPC 1模型系统中的作用 (Aim 3）。这些研究预计将确定使用优化的sHDL靶向细胞内脂质储存 并且调节突变的NPC 1蛋白质稳态将改善疾病表型。此外，我们预计， 证明了少突胶质细胞谱系细胞在NPC神经病理学中的重要但未充分研究的作用。

ABSTRACT Niemann-Pick disease type C (NPC) is an invariably fatal autosomal recessive lipid storage disorder affecting all ages. Patients develop a clinically heterogeneous phenotype that includes severe, progressive neurodegeneration, hepatomegaly, and early death. NPC is commonly caused by loss-of-function mutations in the NPC1 gene (95% of cases), encoding a multipass transmembrane glycoprotein required for exporting unesterified cholesterol from late endosomes and lysosomes. Despite our emerging understanding of the role of NPC1 in intracellular cholesterol trafficking, a diagnosis of NPC remains particularly bleak. There are currently no FDA-approved disease modifying therapies and patients most often die in childhood, reflecting both gaps in our current knowledge of disease pathogenesis and a significant unmet medical need. Our long-term goal is to contribute toward the development of disease-modifying therapies for NPC patients. The next step in attaining this goal is to pursue the overall objective of this application: to define critical targets in CNS disease pathogenesis that can be exploited by drug development efforts. Our central hypothesis is that NPC1 deficiency causes toxicity in both neurons and oligodendrocytes that underlies NPC neuropathology. Moreover, we hypothesize that this toxicity can be rescued by novel therapeutic strategies aimed at reducing the intracellular lipid storage that is characteristic of the disease or by correcting the misfolding of mutant NPC1 protein. These notions are based upon robust preliminary data supporting our model of NPC pathogenesis and the use of innovative therapeutic approaches to rescue disease phenotypes. We will use genetic, biochemical, histological, and phenotypic analyses to: establish the extent to which neuronal lipid storage and toxicity are rescued by optimized synthetic HDL nanoparticles (Aim 1); determine the role of oligodendrocyte lineage cells in NPC neuropathology (Aim 2); and establish effects of proteostasis regulators in humanized NPC1 model systems (Aim 3). These studies are expected to establish that targeting intracellular lipid storage using optimized sHDLs and modulating mutant NPC1 proteostasis will ameliorate disease phenotypes. Moreover, we expect to demonstrate an important, yet under-studied role for oligodendrocyte lineage cells in NPC neuropathology.