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

描述（由申请人提供）：GM1神经节苷脂病是一种由b-半乳糖苷酶缺乏引起的神经退行性溶酶体贮积病，导致GM1神经节苷脂在整个神经系统中积聚。虽然在1881年首次被描述，但神经节苷类药物至今仍无法治愈，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脂质病模型中的真正显著结果支持启动人类临床试验。然而，在临床试验患者中准确评估治疗益处的一个障碍是缺乏用于跟踪疾病进展的客观生物标志物。以下具体目的的目标是使用磁共振成像（MRI）排列来有效评估接受或未接受AAV治疗的神经节脂质病猫的疾病进展（或功能保留）。目的1利用7特斯拉(T) MRI获得猫GM1神经节脂质病脑的连续高分辨率图像。Aim2。用磁共振光谱（MRS）评价神经节脂质病的脑生化。目标3。使用高分辨率核磁共振（NMR）光谱识别神经节脂质病脑中的代谢物谱。申请人的培训将通过主办机构和外部机构提供的MRI短期课程、主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，以及与主办机构、共同主办机构和主要人员的日常互动进行。本方案中的解剖图像将通过7T扫描仪获得，并将对皮层和皮层下目标（如丘脑、尾状核和脑干）进行定量测量。利用MRS，在每只猫的丘脑、额叶皮层、枕叶、颞叶和小脑的水平上测量每只猫的代谢产物，如胍苷乙酸酯或Gal-b(1- 6)Gal-b(1-4)GlcNAc的峰共振，这些低聚糖在GM1神经节脂病脑中已被报道。高分辨率核磁共振波谱将允许对上述脑代谢物和在本研究完成过程中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，该项目将更彻底地表征未经治疗的猫的神经节脂病疾病进展，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.