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

描述(申请人提供)：GM1神经节苷脂沉积症是一种神经退行性溶酶体储存疾病，由b-半乳糖苷酶缺乏引起，导致GM1神经节苷脂在整个神经系统积聚。虽然最早于1881年被描述，但神经节苷脂增多症在今天仍然无法治愈，直到最近5年，成功治疗的希望都很渺茫。猫神经节苷脂沉积症模型中腺相关病毒(AAV)基因治疗的真正显著结果支持了人类临床试验的启动。然而，临床试验患者治疗效益的准确评估的一个障碍是缺乏一个客观的生物标记物来跟踪疾病进展。以下特定目标的目标是使用磁共振成像(MRI)的排列来有效地评估使用或不使用AAV治疗的神经节苷脂沉着症猫的疾病进展(或功能保留)。目的1使用7特斯拉(T)磁共振成像获得猫GM1神经节苷脂沉着症脑的系列高分辨率图像。AIM2.用磁共振波谱(MRS)评估神经节苷脂沉着症的脑生化。目的3.用高分辨率核磁共振波谱鉴定神经节苷脂增多症患者脑内的代谢物。对申请者的培训将通过赞助商和外部机构提供的磁共振短期课程、通过赞助商提供的核磁共振培训、负责任地开展研究单元和研讨会以及与赞助商、共同赞助商和关键人员的日常互动来进行。在目前的提案中，将使用7T扫描仪获取解剖图像，并对皮质和皮质下目标进行定量测量，如丘脑、尾状核和脑干。利用MRS，将在每只猫的丘脑、额叶、枕叶、颞叶和小脑水平上测量代谢产物的峰值共振，例如Gal-b(1-6)Gal-b(1-4)GlcNAc，已在GM1神经节苷脂症脑中报道的寡糖。高分辨率核磁共振波谱将允许对上述大脑代谢物和在完成这项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，该项目将更彻底地描述未经治疗的猫的神经节苷脂沉积症的疾病进展，并评估接受AAV基因治疗的猫的治疗效果。

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.