Advanced MRI biomarkers in HD mouse models translatable to humans: nature history and response to therapeutics

HD 小鼠模型中的先进 MRI 生物标志物可转化为人类：自然史和对治疗的反应

• 批准号: 10665777
• 负责人: Wenzhen Duan
• 金额: $ 65万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10665777
• 关键词: Acceleration; Affect; Age; Atrophic; Basal Ganglia; Behavior assessment; Behavioral; Biological Markers; Biology; Blood; Blood - brain barrier anatomy; Blood Vessels; Brain; Brain Diseases; Brain region; CRISPR/Cas technology; Cerebrum; Clinical; Clinical Trials; Code; Corpus striatum structure; Coupled; Data; Disease; Disease Progression; Early identification; Elements; Event; Functional Magnetic Resonance Imaging; Genes; Goals; Human; Huntington Disease; Huntington gene; Impairment; Inherited; Knock-in Mouse; Length; Lymphatic; Magnetic Resonance Imaging; Measures; Mediating; Metabolic; Metabolism; Monitor; Motor; Movement Disorders; Mus; Nature; Neurodegenerative Disorders; Outcome; Outcome Measure; Oxygen; Pathogenicity; Patients; Phase; Photic Stimulation; Recording of previous events; Relaxation; Reporting; Signal Transduction; Symptoms; System; Techniques; Testing; Therapeutic; Time; Treatment Efficacy; Treatment Protocols; biomarker identification; blood-brain barrier permeabilization; brain metabolism; brain volume; cerebral atrophy; cerebral blood volume; cerebrovascular; clinical diagnosis; detection method; early detection biomarkers; effectiveness evaluation; gain of function; gene therapy; glymphatic dysfunction; glymphatic function; glymphatic system; indexing; lymph flow; lymphatic drainage; lymphatic vessel; magnetic resonance imaging biomarker; metabolic rate; motor symptom; mouse model; multimodality; mutant; neuropathology; neurovascular; neurovascular unit; novel; preclinical study; prevent; protein aggregation; response; treatment effect; treatment response; wasting

Huntington’s disease (HD) is a dominantly inherited, fatal neurodegenerative disorder caused by a CAG expansion in the Huntingtin (HTT) gene. HD preferentially involves the basal ganglia- especially the striatum- but also affects other brain regions and has no cure or disease-modifying treatment yet. Because of its gain-of- function mechanism, strategies to lower mutant HTT are promising as first-ever disease-modifying therapies. Most approaches are currently targeted at manifest HD when clinical outcomes can be used to evaluate the effectiveness. However, as almost 50% of striatal volume has been lost at the time of onset, it would be preferable to begin treatment in the premanifest period before massive loss of striatal volumes. An unmet challenge is how to reliably evaluate therapeutic efficacy in the absence of clinical symptoms as outcome measures. The clinical diagnosis of HD is based on the presence of movement disorders. However, functional changes in the brain can precede motor onset by many years. Neurovascular abnormalities have been reported in premanifest and early HD by us and others. We have reported significantly altered arteriolar CBV (CBVa) in premanifest HD brains, when striatal atrophy was undetectable. We recently found that altered CBVa occurred prior to striatal atrophy in an HD mouse model and that CRISPR/Cas9-mediated mHTT lowering restored CBVa in premanifest HD mice. Collectively, these data suggest reliable measures of neurovascular changes might be valuable biomarkers in premanifest HD. CBV is strongly coupled with brain metabolism, and cerebral metabolic abnormalities are increasingly considered as early neuropathological events in HD. We found impaired response of cerebral metabolism to visual stimulation in premanifest HD patients, correlating with the CAG-Age product (CAP) score, supporting that metabolic disturbances occur at early pathogenic stage and may be another early biomarker for HD. In addition, the recent (re)discovery of brain lymphatic vessels and CSF-lymphatic drainage system illustrates an important brain waste clearance system. Our preliminary data implicate that impairment of elements of this system precedes striatal atrophy and mHTT aggregation in HD mice. The objective of this project is to identify early brain functional changes that rapidly respond to treatment in HD preclinical study by incorporating multimodal advanced MRI measures and to develop sensitive biomarkers translatable to HD clinical trials, particularly in the premanifest period. Aim 1. We will test the hypothesis that mutant HTT impairs cerebral metabolism and alters neurovascular responsivity prior to brain atrophy and behavioral deficits in HD mice. Aim 2. We will assess glymphatic function by measuring lymphatic flow dynamics and BBB permeability in HD mice. Aim 3. We will determine the extent to which metabolic, vascular, and lymphatic MRI measures can monitor the effects of premanifest and manifest treatment of HD mice with CRISPR/Cas9-mediated HTT lowering.

亨廷顿舞蹈症 (HD) 是一种由 CAG 引起的显性遗传性致命性神经退行性疾病 亨廷顿蛋白 (HTT) 基因的扩增优先涉及基底神经节，尤其是纹状体。 但也会影响其他大脑区域，并且由于其增益，目前还没有治愈或缓解疾病的治疗方法。 功能机制、降低突变 HTT 的策略有望成为首个疾病缓解疗法。 目前大多数方法都针对明显的 HD，此时可以使用临床结果来评估 HD 然而，由于在发病时几乎 50% 的纹状体体积已丢失，因此效果可能会很差。 最好在纹状体体积大量损失之前开始治疗。 挑战是如何在没有临床症状作为结果的情况下可靠地评估治疗效果 HD 的临床诊断基于运动障碍的存在。 大脑的变化可能比运动发生早很多年。 我们和其他人在预发病和早期 HD 中报告了小动脉 CBV 的显着改变。 (CBVa) 在HD大脑中，当纹状体萎缩无法检测到时，我们最近发现这种改变。 在 HD 小鼠模型中，CBVa 发生在纹状体萎缩之前，并且 CRISPR/Cas9 介导的 mHTT 总体而言，这些数据表明了 HD 小鼠恢复的 CBVa 的可靠测量。 神经血管变化可能是 HD 前期 CBV 与大脑密切相关的有价值的生物标志物。 代谢和脑代谢异常越来越被认为是早期神经病理学 我们发现 HD 前期的大脑代谢对视觉刺激的反应受损。 患者，与 CAG-Age 乘积 (CAP) 评分相关，支持代谢紊乱发生在 早期致病阶段，可能是 HD 的另一个早期生物标志物。此外，最近（重新）发现了 HD。 脑淋巴管和脑脊液淋巴引流系统说明了脑废物清除的重要作用 我们的初步数据表明，该系统的元素受损先于纹状体萎缩。 和 mHTT 聚集在 HD 小鼠中 该项目的目的是识别早期大脑功能变化。 通过结合多模态先进 MRI 措施，对 HD 临床前研究中的治疗做出快速反应 并开发可转化为 HD 临床试验的敏感生物标志物，特别是在发病前阶段。 目标 1. 我们将检验突变 HTT 损害脑代谢并改变神经血管的假设 HD 小鼠脑萎缩和行为缺陷之前的反应性。目标 2。我们将评估类淋巴管。 通过测量 HD 小鼠的淋巴流动动力学和 BBB 通透性来确定功能。目标 3。我们将确定。 代谢、血管和淋巴 MRI 测量可以在多大程度上监测预显性的影响 以及通过 CRISPR/Cas9 介导的 HTT 降低对 HD 小鼠进行明显的治疗。