OXYSTEROL BIOMARKERS FOR NIEMANN-PICK C DISEASE

描述（由申请方提供）：C1型尼曼-皮克病（NPC 1）是一种罕见的进行性神经退行性疾病，其特征为胆固醇和其他脂质在内脏和中枢神经系统中蓄积。NPC 1疾病治疗开发的障碍是缺乏易于量化的结果指标来评估临床试验中治疗的疗效。通过广泛的代谢组学研究，我们在NPC 1受试者中发现了胆固醇氧化产物（“氧固醇”）生物标志物，其反映了氧化应激和未酯化胆固醇储存的独特交叉-NPC 1疾病的生化标志。该提案测试了高度创新的假设，即氧固醇生物标志物与其他胆固醇稳态标志物一起可以作为评估疾病修饰疗法（例如，2-羟丙基-β-环糊精（HP-β-CD）对CNS中胆固醇代谢的影响，并监测疾病进展。24（S）-HC（几乎仅在CNS的大型神经元中合成）和CSF胆固醇酯（CE）提供了潜在的定量、非侵入性指标，以指导给药和监测药物反应。同样，胆甾烷-3，5，6-三醇（“三醇”），我们以前已经证明在NPC 1受试者的CSF中升高，将告知HP-β-CD对神经元内胆固醇储存的影响。这一假设将在脑室内（ICV）HP-β-CD给药的NPC 1动物模型（Aim 1）、参加自然史研究的NPC 1人类受试者和NIH临床中心的ICV HP-β-CD 1期试验（Aim 2）中进行检验。该提案还将探索利用三醇检测的特殊受试者工作特征（ROC）开发新生儿筛查的可能性，以更早地识别NPC 1患者，从而干预症状前患者（目标3）。建议的NPC 1疾病的新生儿筛查是创新的，将是第一个非酶溶酶体疾病，以及第一个固醇代谢的先天性缺陷。虽然该项目的目标是开发适用于在全州或区域水平实施的NPC 1疾病的原型新生儿筛查，但为提取和检测氧固醇而开发的串联质谱法可以容易地扩展到在其他固醇疾病中积累的代谢物（例如，Smith-Lemli-Opitz综合征），从而允许在单一筛选的背景下对几种遗传性疾病进行多重筛选。该提案中的研究非常重要，因为我们解决了NPC 1疾病的关键未满足的治疗和诊断需求。

DESCRIPTION (provided by applicant): Niemann-Pick type C1 (NPC1) disease is a rare, progressive neurodegenerative disorder characterized by accumulation of cholesterol and other lipids in the viscera and central nervous system. A barrier to the development of treatments for NPC1 disease is the lack of readily quantifiable outcome measures to evaluate efficacy of therapy in clinical trials. Through broad-based metabolomic efforts, we have discovered in NPC1 subjects cholesterol oxidation product ("oxysterol") biomarkers that reflect the unique intersection of oxidative stress and unesterified cholesterol storage - the biochemical hallmark of NPC1 disease. This proposal tests the highly innovative hypothesis that oxysterol biomarkers, together with other cholesterol homeostatic markers, can serve as outcome measures to assess the effect of disease-modifying therapies (e.g., 2-hydroxypropyl-�-cyclodextrin, HP-�-CD) on cholesterol metabolism in the CNS and to monitor disease progression. 24(S)-HC, which is synthesized almost exclusively in large neurons in the CNS, and CSF cholesteryl esters (CE) offer potential quantitative, non-invasive metrics to guide dosing and to monitor drug response. Likewise, cholestane-3�, 5�, 6�-triol ("triol"), which we have previously shown to be elevated in the CSF of NPC1 subjects, will inform with respect to the effect of HP-�-CD on intraneuronal cholesterol storage. This hypothesis will be tested in NPC1 animal models administered intracerebroventricular (ICV) HP-�-CD (Aim 1), and in NPC1 human subjects enrolled in a natural history study and in a Phase 1 trial for ICV HP-�-CD at the NIH Clinical Center (Aim 2). The proposal will also explore the possibility that the exceptional receiver operating characteristics (ROC) of the triol assay can be harnessed to develop a newborn screen to identify NPC1 patients earlier and thus intervene in pre-symptomatic patients (Aim 3). The proposed newborn screen for NPC1 disease is innovative and would be the first for a non-enzymatic lysosomal disorder, as well as the first for an inborn error of sterol metabolism. While the goal of this project is to develop a prototype newborn screen for NPC1 disease suitable for implementation at the statewide or regional level, the tandem mass spectrometry methods developed for extraction and detection of the oxysterols could be readily extended to metabolites that accumulate in other sterol disorders (e.g., Smith-Lemli-Opitz Syndrome), thereby permitting multiplexed screening for several inherited disorders within the context of a single screen. The studies in this proposal are highly significant because we address the critical unmet therapeutic and diagnostic needs of NPC1 disease.