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神经节病是由B-半乳糖苷酶的酶缺乏引起的神经退行性溶酶体储存疾病，导致整个神经系统中GM1神经节蛋白的积累。尽管在1881年首次描述，但今天的神经节剂仍无法治愈，直到最近5年，成功的治疗几乎没有希望。猫节神经节病模型中与腺相关病毒（AAV）基因疗法的真正显着结果支持人类临床试验的启动。但是，在临床试验患者中准确评估治疗益处的障碍是他缺乏跟踪疾病进展的客观生物标志物。以下特定目的的目的是使用磁共振成像（MRI）的排列来有效评估有或没有AAV治疗的神经节病猫中疾病进展（或功能的保留）。 AIM.1使用7 Tesla（T）MRI获得猫GM1神经节病大脑的串行高分辨率图像。 AIM2。用MR光谱法（MRS）评估神经节病中的脑生物化学。 AIM 3。使用高分辨率核磁共振（NMR）光谱识别神经节病大脑中的代谢产物谱。申请人的培训将通过赞助和外部机构提供的MRI简短课程，通过赞助商机构进行核磁共振培训，负责任的研究模块和研讨会的负责人，以及与赞助商，共同赞助者和关键人员的日常互动。当前建议中的解剖图像将使用7T扫描仪获取，并将对皮质和皮层下靶标进行定量测量，例如丘脑，尾状核和脑干。使用MRS，将在GM1神经节病大脑中报道的瓜尼替酸或GAL-B（1-6）GAL-B（1-4）GAL-B（1-6）GAL-B（1-4）GAL-B（1-4）GAL-B（1-6）GAL-B（1-6）GAL-B（1-6）的峰值共振，将在每种饮料中测量的寡糖，thalamus，Frontal Cortex，cottipital lebe，extremal lobe and exereal lobe。高分辨率NMR光谱法将允许对上述脑代谢产物以及本研究完成期间遇到的任何新型代谢产物进行定量分析。通过使用基于磁共振的技术，该项目将更彻底地表征未经处理的猫中的神经节病疾病进展，并评估AAV基因治疗治疗的猫的治疗益处。