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: 10516483
• 负责人: Wenzhen Duan
• 金额: $ 68.45万
• 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/10516483
• 关键词: 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; Elements; Event; Functional Magnetic Resonance Imaging; Genes; Goals; Human; Human Characteristics; Huntington Disease; Huntington gene; Huntington protein; Impairment; Inherited; Knock-in Mouse; Length; Lymphatic; Magnetic Resonance Imaging; Measures; Mediating; Metabolic; Metabolism; Monitor; Motor; Movement Disorders; Mus; Neurodegenerative Disorders; Outcome; Outcome Measure; Oxygen; Pathogenicity; Patients; Phase; Photic Stimulation; Proteins; Recording of previous events; Relaxation; Reporting; Signal Transduction; Symptoms; System; Techniques; Testing; Therapeutic; Time; Treatment Efficacy; Treatment Protocols; base; blood-brain barrier permeabilization; brain metabolism; brain volume; cerebral atrophy; cerebral blood volume; cerebrovascular; clinical diagnosis; 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; 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.

亨廷顿氏病（HD）是由CAG引起的主要遗传的致命神经退行性疾病 Huntingtin（HTT）基因的扩张。高清优先涉及巴萨神经节 - 尤其是纹状体 但也影响其他大脑区域，尚无治愈或疾病改良治疗。因为它的收益 功能机制，降低突变体HTT的策略被承诺为有史以来修改疾病的疗法。 当临床结果可用于评估临床结果时，目前大多数方法都是针对明显HD的 效力。但是，由于在发作时近50％的纹状体量已经丢失，这将是 在大规模纹状体量损失之前，最好是在较前时期开始治疗。一个未满足的 挑战是如何在没有临床症状的情况下可靠地评估治疗效率 措施。 HD的临床诊断基于运动障碍的存在。但是，功能性 大脑的变化可以在运动开始之前多年。神经血管异常已经 我们和其他人在Premanifest和早期的高清报告中报告。我们报道了小动脉CBV的显着改变 （CBVA）在纹状体萎缩是无法检测的时，在premifest HD大脑中。我们最近发现发生了变化 CBVA发生在HD鼠标模型中的纹状体萎缩之前，该CRISPR/CAS9介导的MHTT 降低了Premanifest HD小鼠的恢复CBVA。总的来说，这些数据提出了可靠的措施 神经血管变化可能是premifest HD的宝贵生物标志物。 CBV与大脑强烈结合 代谢和脑代谢异常被越来越多地视为早期神经病理学 高清活动。我们发现大脑代谢对前命中率HD视觉刺激的反应受损 患者与CAG-AGE产品（CAP）分数相关，支持代谢灾害发生在 早期致病阶段，可能是HD的另一个早期生物标志物。此外，最近发现 脑淋巴视频和CSF淋巴引流系统说明了重要的脑部废物清除 系统。我们的初步数据暗示，该系统元素的损害在纹状体萎缩之前 HD小鼠中的MHTT聚集。该项目的目的是确定早期大脑功能变化 通过纳入多模式高级MRI测量，可以快速响应HD临床前研究中的治疗 并开发可转换为高清临床试验的敏感生物标志物，尤其是在premanifest时期。 目的1。我们将检验以下假设：突变体HTT损害脑代谢并改变神经血管 在脑萎缩之前的反应性和行为性在HD小鼠中定义。 AIM 2。我们将评估糖含量 通过测量HD小鼠中淋巴流动动力学和BBB渗透性的功能。目标3。我们将确定 代谢，血管和淋巴MRI测量的程度可以监测premifest的影响 以及用CRISPR/CAS9介导的HTT降低的HD小鼠的明显治疗。