Decoding cerebrospinal fluid huntingtin biomarkers

解码脑脊液亨廷顿生物标志物

• 批准号: 10670547
• 负责人: Amber L Southwell
• 金额: $ 4.9万
• 依托单位: UNIVERSITY OF CENTRAL FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2023-05-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10670547
• 关键词: Active Biological Transport; Acute Brain Injuries; Address; Alleles; Antisense Oligonucleotides; Basal Ganglia; Biological Markers; Blood; Brain; Brain region; British Columbia; Cell physiology; Cells; Cerebrospinal Fluid; Clinic; Clinical; Clinical Treatment; Clinical Trials; Collection; Complex; Data; Data Analyses; Development; Discrimination; Disease; Disease Progression; Dose; Eligibility Determination; Flow Cytometry; Goals; Health; Huntington Disease; Huntington gene; Immunoprecipitation; Individual; Intervention; Kinetics; Knowledge; Longitudinal Studies; Longitudinal cohort; Measurement; Measures; MicroRNAs; Monitor; Mus; Nerve Degeneration; Neurons; Onset of illness; Participant; Pathway interactions; Patients; Phase; Placebos; Plasma; Predictive Value; Proteins; Sampling; Source; Structure; System; Therapeutic; Time; Tissues; Universities; Viral Vector; Work; biobank; brain cell; cell type; clinical trial participant; detection assay; extracellular; glymphatic clearance; glymphatic system; injured; man; mutant; neuroprotection; novel; phenotypic data; pre-clinical; tool

PROJECT SUMMARY The goal of this project is to functionalize quantitation of cerebrospinal fluid (CSF) huntingtin (HTT) protein as a Huntington disease (HD) biomarker. The first Phase I/IIa HTT lowering clinical trial for the treatment of HD recently concluded demonstrating dose-dependent reduction of mutant HTT (mtHTT) protein in the CSF of treated patients. The use of this measure was based on our previous work using a novel ultrasensitive mtHTT detection assay to demonstrate that suppression of HTT in the entire mouse CNS results in correlative reduction of CSF mtHTT, but further studies are required for meaningful use of this measure in the clinic. The therapeutic under trial is expected to mostly be active in superficial brain regions, while other strategies in development are expected to mostly be active in deeper brain regions or specific cell types. For this reason, it is necessary to know the regional and cell type contributions to CSF mtHTT in order to predict what a treatment-induced change means for the targeted tissue(s). Comparison of brain and CSF mtHTT in mice that express mtHTT everywhere except the brain region or cell type at study to those with ubiquitous mtHTT expression will be used to discern the proportional contributions to CSF mtHTT and provide a way to infer magnitude of treatment-induced changes in the brain by those in CSF. It will also be necessary to know how mtHTT enters CSF. Comparison of brain and CSF HTT in systems with and without neurodegeneration will be used to distinguish passive release of HTT as cells die and break open from active transport of HTT to CSF. Furthermore, the kinetics of brain clearance of mtHTT will be delineated by ectopic delivery of intra- or extracellular mtHTT protein directly to the brains of mice and subsequent measurement of brain, CSF, and plasma mtHTT at multiple post-delivery time points. Perturbation of HTT secretion and the glymphatic system will be used to investigate how mtHTT moves from inside cells of the brain to the CSF and eventually the blood. Concurrently, mtHTT will be quantified in longitudinal CSF and plasma samples from HD patients and controls and compared to phenotypic data to determine how biofluid mtHTT changes over typical clinical trial intervals and with progression in individuals, thus separating time- and treatment-dependent changes. This will also determine if CSF mtHTT concentration can be used to more accurately predict disease conversion and progression. We will also attempt to quantify wtHTT protein in CSF to investigate potential extracellular functions of HTT as well as enable allelic discrimination for trials of selective agents. The results of these studies will provide the necessary basis to interpret clinical quantitation of CSF HTT, determine which types of therapeutics could be effectively evaluated by this measure, and ascertain the predictive value of longitudinal CSF HTT quantitation in monitoring HD progression and selecting clinical trial participants.

项目概要 该项目的目标是将脑脊液 (CSF) 亨廷顿蛋白 (HTT) 蛋白的定量功能化，作为一种 亨廷顿病 (HD) 生物标志物。第一个降低 HTT 治疗 HD 的 I/IIa 期临床试验 最近得出结论，证明脑脊液中突变 HTT (mtHTT) 蛋白的剂量依赖性减少 接受治疗的患者。该措施的使用基于我们之前使用新型超灵敏 mtHTT 的工作 检测试验证明抑制整个小鼠中枢神经系统中的 HTT 会导致相关减少 CSF mtHTT，但需要进一步研究才能在临床上有意义地使用该措施。治疗性的 正在试验中预计主要活跃于浅层大脑区域，而其他正在开发的策略是 预计主要在更深的大脑区域或特定细胞类型中活跃。为此，有必要 了解区域和细胞类型对 CSF mtHTT 的贡献，以预测治疗引起的变化 用于目标组织的手段。各处表达 mtHTT 的小鼠大脑和脑脊液 mtHTT 的比较 除了研究中的大脑区域或细胞类型外，那些具有普遍存在的 mtHTT 表达的细胞将被用来辨别 对 CSF mtHTT 的贡献比例，并提供一种推断治疗引起的变化幅度的方法 脑脊液中的细胞在大脑中。还需要了解 mtHTT 如何进入 CSF。大脑和大脑的比较 存在和不存在神经变性的系统中的 CSF HTT 将用于区分 HTT 的被动释放： 细胞因 HTT 主动转运至脑脊液而死亡并破裂。此外，大脑清除的动力学 mtHTT 将通过将细胞内或细胞外 mtHTT 蛋白直接异位递送至小鼠大脑来描绘 以及随后在多个产后时间点测量大脑、脑脊液和血浆 mtHTT。 HTT 分泌和类淋巴系统的扰动将用于研究 mtHTT 如何从 大脑细胞内部到脑脊液，最后到血液。同时，mtHTT 将纵向量化 来自 HD 患者和对照的脑脊液和血浆样本，并与表型数据进行比较，以确定如何 生物流体 mtHTT 在典型的临床试验间隔内以及随着个体的进展而变化，从而将 时间和治疗依赖性的变化。这也将确定 CSF mtHTT 浓度是否可用于 更准确地预测疾病的转化和进展。我们还将尝试量化 wtHTT 蛋白 CSF 将研究 HTT 的潜在细胞外功能，并为试验进行等位基因区分 选择剂。这些研究的结果将为解释临床定量提供必要的基础 CSF HTT，确定哪些类型的治疗方法可以通过该措施有效评估，并确定 纵向脑脊液 HTT 定量在监测 HD 进展和选择临床试验中的预测价值 参与者。