In vivo magnetic resonance-based analysis of inherited neurologic disease after g

基于体内磁共振的遗传性神经系统疾病分析

• 批准号: 8657391
• 负责人: Heather L Gray-Edwards
• 金额: $ 6.55万
• 依托单位: AUBURN UNIVERSITY AT AUBURN
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8657391
• 关键词: 5 year old; Affect; Anatomy; Animal Model; Animals; Area; Attenuated; Autopsy; Biochemistry; Biological Markers; Brain; Brain Stem; Cell Death; Cerebellum; Child; Choline; Clinical Trials; Creatine; Dependovirus; Detection; Deterioration; Disease; Disease Progression; Enzymes; Family Felidae; Felis catus; Galactosidase; Ganglioside GM1; Gangliosides; Gangliosidoses; Gangliosidoses GM2; Gangliosidosis GM1; Gastric Feeding Tubes; Goals; Human; Human Resources; Image; Inherited; Institution; Lysosomal Storage Diseases; Magnetic Resonance; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Mass Spectrum Analysis; Measurement; Measures; Modeling; Molecular; Monitor; N-acetylaspartate; NMR Spectroscopy; Nerve Degeneration; Nervous system structure; Neurologic; Neurons; Nuclear Magnetic Resonance; Occipital lobe; Oligosaccharides; Patients; Publishing; Reporting; Resolution; Sandhoff Disease; Spectrum Analysis; Staging; Structure; Taurine; Technology; Temporal Lobe; Terminal Disease; Testing; Thalamic structure; Therapeutic; Tissues; Training; Urine; Vegetative States; Viral; Viral Genes; Water; base; brain size; caudate nucleus; enzyme deficiency; frontal lobe; gene therapy; guanidinoacetate; imaging modality; in vivo; meetings; mouse model; myoinositol; novel; public health relevance; responsible research conduct; therapeutic evaluation

DESCRIPTION (provided by applicant): GM1 gangliosidosis is a neurodegenerative lysosomal storage disease caused by an enzyme deficiency in b- galactosidase that results in buildup of GM1 ganglioside throughout the nervous system. Though first described in 1881, the gangliosidoses remain incurable today and, until the last 5 years, little hope for a successful treatment has been forthcoming. Truly remarkable results of adeno-associated viral (AAV) gene therapy in the feline gangliosidosis models support the initiation of human clinical trials. However, a barrier to the accurate evaluation of therapeutic benefit in clinical trial patients is he lack of an objective biomarker with which to track disease progression. The goal of the following specific aims is to use permutations of magnetic resonance imaging (MRI) to effectively evaluate disease progression (or retention of function) in gangliosidosis cats with or without AAV treatment. Aim.1 Obtain serial high resolution images of the feline GM1 gangliosidosis brain using a 7 Tesla (T) MRI. Aim2. Evaluate brain biochemistry in gangliosidosis with MR spectroscopy (MRS). Aim 3. Identify metabolite profiles in the gangliosidosis brain using high resolution nuclear magnetic resonance (NMR) spectroscopy. Training of the applicant will be conducted through MRI short courses offered by the sponsoring and external institutions, nuclear magnetic resonance training through the sponsor institution, Responsible Conduct of Research modules and seminars, and daily interactions with the sponsor, co-sponsor and key personnel. Anatomical images in the current proposal will be acquired with the 7T scanner and quantitative measurements will be taken of cortical and subcortical targets such as the thalamus, caudate nucleus and brain stem. Using MRS, peak resonances from metabolites such as guanidinoacetate or Gal-b(1- 6)Gal-b(1-4)GlcNAc, oligosaccharides that have been reported in GM1 gangliosidosis brain, will be measured in each cat at the level of thalamus, frontal cortex, occipital lobe, temporal lobe and cerebellum. High resolution NMR spectroscopy will allow for quantitative analysis of brain metabolites described above and any novel metabolites encountered during the completion of this study. Through the use of magnetic resonance-based technology, this project will more thoroughly characterize gangliosidosis disease progression in untreated cats and evaluate therapeutic benefit in cats treated by AAV gene therapy.

描述（由申请人提供）：GM1 神经节苷脂贮积症是一种神经退行性溶酶体贮积病，由 β-半乳糖苷酶缺乏引起，导致 GM1 神经节苷脂在整个神经系统中积聚。尽管神经节苷脂病于 1881 年首次被描述，但至今仍无法治愈，而且直到最近 5 年，成功治疗的希望仍然渺茫。腺相关病毒（AAV）基因治疗在猫神经节苷脂沉积症模型中取得的真正显着结果支持了人体临床试验的启动。然而，准确评估临床试验患者的治疗效果的障碍是缺乏跟踪疾病进展的客观生物标志物。以下具体目标的目的是利用磁共振成像 (MRI) 的排列来有效评估接受或不接受 AAV 治疗的神经节苷脂病猫的疾病进展（或功能保留）。目标.1 使用 7 特斯拉 (T) MRI 获得猫 GM1 神经节苷脂沉积症大脑的连续高分辨率图像。目标2。使用磁共振波谱 (MRS) 评估神经节苷脂沉积症的脑生物化学。目标 3. 使用高分辨率核磁共振 (NMR) 光谱鉴定神经节苷脂沉积症大脑中的代谢物谱。申请人的培训将通过申办者和外部机构提供的 MRI 短期课程、申办机构提供的核磁共振培训、负责任的研究行为模块和研讨会以及与申办者、共同申办者和关键人员的日常互动进行。当前提案中的解剖图像将使用 7T 扫描仪获取，并对丘脑、尾状核和脑干等皮质和皮质下目标进行定量测量。使用 MRS，将在每只猫的丘脑水平上测量代谢物的峰值共振，例如胍基乙酸盐或 Gal-b(1-6)Gal-b(1-4)GlcNAc（已在 GM1 神经节苷脂沉积症大脑中报道的寡糖） 、额叶皮质、枕叶、颞叶和小脑。高分辨率核磁共振波谱将允许对上述脑代谢物以及在完成本研究期间遇到的任何新代谢物进行定量分析。通过使用基于磁共振的技术，该项目将更全面地描述未经治疗的猫的神经节苷脂病的进展情况，并评估接受 AAV 基因治疗的猫的治疗效果。