Therapeutic targets for Niemann-Pick type C neurodegeneration

尼曼-皮克 C 型神经变性的治疗靶点

基本信息

批准号：
10271742
负责人：
ANDREW P LIEBERMAN
金额：
$ 56.31万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-15 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10271742
关键词：
Adult Affect Age Agonist Alleles Behavioral Biochemical Biological Models Cell Lineage Cell Maturation Cells Central Nervous System Diseases Cessation of life Characteristics Childhood Cholesterol Clinical Complement Data Defect Development Diagnosis Disease Dose FDA approved Formulation Future Gene Expression Genetic Glycoproteins Goals Hepatomegaly High Density Lipoproteins Histologic Human Impairment In Vitro Injections Knowledge Ligands Lipids Lysosomes Maintenance Medical Missense Mutation Modeling Monitor Mus Mutant Strains Mice Myelin NPC1 gene Nerve Degeneration Neuronal Dysfunction Neurons Nuclear RNA Oligodendroglia Pathogenesis Pathway interactions Patients Peptides Phenotype Proteins Public Health Role Series Supraoptic Vertical Ophthalmoplegia Testing Therapeutic Toxic effect Translating Work base cholesterol trafficking disease phenotype drug development dysmyelination efficacy clinical trial humanized mouse innovation knock-down late endosome loss of function mutation mutant myelination nanoparticle nerve stem cell neuron loss neuropathology neurotoxicity novel strategies novel therapeutic intervention oligodendrocyte lineage oligodendrocyte progenitor preclinical efficacy progressive neurodegeneration protein folding protein transport proteostasis small molecule stem cells therapeutic target trafficking transcription factor transcriptome sequencing

项目摘要

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.

抽象的 Niemann-Pick疾病C型（NPC）是一种致命的致命常染色体隐性脂质储存障碍，影响了所有人年龄。患者发展出临床上异质的表型，包括严重的进行性神经变性，肝肿大和早死亡。 NPC通常是由功能丧失突变引起的 NPC1基因（占病例的95％），编码出口所需的多轴跨膜糖蛋白来自晚期内体和溶酶体的未酯化胆固醇。尽管我们有了我们对角色的理解 NPC1在细胞内胆固醇运输中，NPC的诊断仍然特别黯淡。目前有没有FDA批准的疾病修饰疗法，患者通常在童年时期死亡，反映出这两个差距我们目前对疾病发病机理的了解和巨大的未满足医疗需求。我们的长期目标是为NPC患者的疾病改良疗法的发展做出贡献。下一步达到这个目标是追求此应用的总体目标：定义中枢神经系统疾病的关键目标药物开发工作可以利用的发病机理。我们的中心假设是NPC1缺乏症引起NPC神经病理学基础的神经元和少突胶质细胞的毒性。而且，我们假设可以通过旨在减少细胞内的新型治疗策略来挽救这种毒性脂质储存是该疾病的特征或通过纠正突变NPC1蛋白的错误折叠。这些概念基于强大的初步数据，支持我们的NPC发病机理模型和使用挽救疾病表型的创新治疗方法。我们将使用遗传，生化，组织学，和表型分析到：确定神经元脂质储存和毒性的程度优化的合成HDL纳米颗粒（AIM 1）；确定少突胶质细胞在NPC中的作用神经病理学（目标2）；并在人源化NPC1模型系统中建立蛋白质量调节剂的影响（目标3）。预计这些研究将确定使用优化的SHDL靶向细胞内脂质储存调节突变体NPC1蛋白抑制作用将改善疾病表型。而且，我们希望在NPC神经病理学中，表现出对少突胶质细胞细胞的重要但研究不足的作用。