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

描述（由申请方提供）：GM 1神经节苷脂沉积症是一种神经退行性溶酶体贮积病，由B-半乳糖苷酶缺乏引起，导致GM 1神经节苷脂在整个神经系统中积聚。虽然首次描述于1881年，但神经节苷脂沉积症今天仍然无法治愈，直到最近5年，成功治疗的希望渺茫。腺相关病毒（AAV）基因治疗在猫神经节苷脂沉积症模型中的真正显著结果支持人类临床试验的启动。然而，在临床试验患者中准确评估治疗益处的障碍是缺乏用于跟踪疾病进展的客观生物标志物。以下具体目标的目的是使用磁共振成像（MRI）的排列来有效评价有或无AAV治疗的神经节苷脂沉积症猫的疾病进展（或功能保留）。目的：1使用7特斯拉（T）MRI获得猫GM 1神经节苷脂沉积症脑的系列高分辨率图像。目标2。用磁共振波谱（MRS）评价神经节苷脂沉积症的脑生化。目标3。使用高分辨率核磁共振（NMR）光谱法鉴定神经节苷脂沉积症脑中的代谢产物谱。将通过申办者和外部机构提供的MRI短期课程、申办者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，对申请人进行培训。当前提案中的解剖图像将使用7 T扫描仪采集，并对皮质和皮质下目标（如丘脑、尾状核和脑干）进行定量测量。使用MRS，将在每只猫的丘脑、额叶皮质、枕叶、颞叶和小脑水平测量代谢物（如胍基乙酸盐或Gal-b（1- 6）Gal-b（1-4）GlcNAc，GM 1神经节苷脂沉积症脑中报告的寡糖）的峰共振。高分辨率NMR光谱学将允许定量分析上述脑代谢物和本研究完成期间遇到的任何新代谢物。通过使用基于磁共振的技术，该项目将更彻底地表征未经治疗的猫的神经节苷脂沉积病疾病进展，并评估通过AAV基因治疗治疗的猫的治疗益处。

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.