Therapeutic Targets for Niemann-Pick Type C Neurodegeneration

摘要 C型尼曼-皮克病(NPC)是一种致命的常染色体隐性脂肪储存障碍，影响所有 年龄。患者出现临床上的异质性表型，包括严重的、进行性的 神经变性、肝肿大和过早死亡。鼻咽癌通常是由功能缺失突变引起的 NPC1基因(95%的病例)，编码出口所需的多通道跨膜糖蛋白 来自晚期内切体和溶酶体的未酯化胆固醇。尽管我们正在逐渐认识到 NPC1在细胞内胆固醇转运方面，对鼻咽癌的诊断仍然尤为黯淡。目前有 没有FDA批准的疾病修改疗法，患者大多在儿童时期死亡，这反映了 我们目前对疾病发病机制的了解以及一个重大的未得到满足的医学需求。我们的长期目标是 为鼻咽癌患者疾病修正疗法的发展做出贡献。实现的下一步是 此目标旨在实现此应用程序的总体目标：定义中枢神经系统疾病的关键靶点 可以通过药物开发工作来利用的致病机制。我们的中心假设是NPC1缺乏 对神经元和少突胶质细胞造成毒性，这是鼻咽癌神经病理学的基础。此外，我们 假设这种毒性可以通过旨在减少细胞内毒素的新治疗策略来挽救 脂肪储存是疾病的特征，或者通过纠正突变的NPC1蛋白的错误折叠来实现。这些 这些概念是基于强有力的初步数据支持我们的鼻咽癌发病机制模型和使用 拯救疾病表型的创新治疗方法。我们将利用遗传学、生化、组织学、 和表型分析：建立神经元脂质储存和毒性被拯救的程度 优化的合成高密度脂蛋白纳米粒(目标1)；确定少突胶质细胞系细胞在鼻咽癌中的作用 神经病理学(目标2)；并在人源化的NPC1模型系统中建立蛋白平衡调节剂的作用 (目标3)。这些研究有望确定使用优化的sHDL靶向细胞内脂类存储 调节突变型NPC1蛋白平衡将改善疾病表型。此外，我们预计将 展示了少突胶质细胞系细胞在鼻咽癌神经病理学中的重要作用，但研究不足。

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.