Biomarkers for Disease Severity and Therapeutic Response in LINCL

我们的假设是，先进的磁共振成像(MRI)技术与 定量评价脑脊液(CSF)代谢物可以开发一种全面的 一套评估婴幼儿晚期疾病严重程度和治疗反应的生物标志物 神经性蜡样脂褐素沉积症(LINCL)。我们工作的最终目的是准确客观地评估 治疗效果，从而改善LINCL受试者的医疗管理，特别是作为新的 LINCL的治疗选择变得可用。我们的具体目标是开发一种成像生物标志物小组 用于评估LINCL疾病严重程度和在单个亚结构水平上的治疗反应 并与脑脊液代谢组学结果进行比较。 我们的具体目标如下：目标1)开发脑区特异性磁共振成像 生物标志物面板，包括扩散系数、扩散分数各向异性、T2弛豫时间、T2* 松弛时间、脑脊液体积百分比和质子光谱代谢物比率。我们会 在注册时，对对照组中16名LINCL受试者的30多个大脑区域进行检查，然后再次进行 18个月后。目的2：建立一种脑脊液代谢产物生物标记物小组，包括对Over的评估 1000种化合物，并测试其与MRI生物标记物、疾病严重程度的临床指标以及 受试者年龄。对照组16例LINCL患者经腰穿采集脑脊液 在接受基因治疗的前一天和18个月后再次在麻醉下进行。 目的：应用MRI生物标记物评价AAVRH.10介导的AAVRH.10治疗效果。 LINCL的基因治疗。治疗组中的16名受试者将在5个MRI时间点进行检查， 包括筛查时，给药前一天，以及在6、12和18岁时 治疗后几个月。

Our hypothesis is that advanced magnetic resonance imaging (MRI) techniques in combination with the quantitative evaluation of cerebrospinal fluid (CSF) metabolites can be exploited to develop a comprehensive set of biomarkers for assessing disease severity and therapeutic response in children with late infantile neuronal ceroid lipofuscinosis (LINCL). The ultimate goal of our work is to accurately and objectively assess therapeutic efficacy and thereby improve the medical management of LINCL subjects, especially as new treatment options for LINCL become available. Our specific goal is to develop an imaging biomarker panel for assessing LINCL disease severity and therapeutic response at the level of individual substructures in the brain, and compare this with the results of CSF metabolomics. Our Specific Aims are as follows: Aim 1) To develop a brain-region-specific magnetic resonance imaging biomarker panel, including diffusion coefficients, diffusion fractional anisotropy, T2 relaxation times, T2* relaxation times, the volume percentage of CSF, and proton spectroscopic metabolite ratios. We will examine over 30 brain regions in 16 LINCL subjects in a control group at the time of enrollment, and again 18 months later. Aim 2: To develop a CSF metabolite biomarker panel that includes the evaluation of over 1000 compounds, and test its correlation with the MRI biomarkers, clinical indicators of disease severity, and subject age. CSF will be collected from the 16 LINCL subjects in the control group via lumbar puncture performed under anesthesia at one day prior to administration of gene therapy and again 18 months later. Aim 3: To apply the MRI biomarker panel in the evaluation of therapeutic efficacy of AAVrh.10 mediated gene therapy for LINCL. Sixteen subjects in a treatment group will be examined at 5 MRI time points, including at the time of screening, one day before administration of therapy, and again at 6, 12 and 18 months post therapy.