Biomarkers for Disease Severity and Therapeutic Response in LINCL

LINCL 疾病严重程度和治疗反应的生物标志物

• 批准号: 9146689
• 负责人: DOUGLAS J BALLON
• 金额: $ 7.28万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9146689
• 关键词: Age; Anesthesia procedures; Anisotropy; Biological Markers; Brain; Brain region; CLN2 gene; Cerebrospinal Fluid; Chemicals; Child; Clinical; Control Groups; Data Set; Diffusion; Disease; Enrollment; Evaluation; Gene therapy trial; Goals; Grant; Harvest; Image; Imaging Techniques; Individual; Institution; Instruction; Jansky-Bielschowsky Disease; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Medical; Protons; Quantitative Evaluations; Recruitment Activity; Relaxation; Serotyping; Severity of illness; Spinal Puncture; Testing; Therapy Clinical Trials; Therapy trial; Time; Treatment Efficacy; Work; adeno-associated viral vector; biomarker panel; cohort; gene therapy; imaging biomarker; imaging modality; improved; metabolomics; novel; novel diagnostics; prospective; screening; tool; treatment group; treatment response; tv watching; Age; Anesthesia procedures; Anisotropy; Biological Markers; Brain; Brain region; CLN2 gene; Cerebrospinal Fluid; Chemicals; Child; Clinical; Control Groups; Data Set; Diffusion; Disease; Enrollment; Evaluation; Gene therapy trial; Goals; Grant; Harvest; Image; Imaging Techniques; Individual; Institution; Instruction; Jansky-Bielschowsky Disease; Magnetic Resonance Imaging; Measurement; Measures; Mediating; Medical; Protons; Quantitative Evaluations; Recruitment Activity; Relaxation; Serotyping; Severity of illness; Spinal Puncture; Testing; Therapy Clinical Trials; Therapy trial; Time; Treatment Efficacy; Work; adeno-associated viral vector; biomarker panel; cohort; gene therapy; imaging biomarker; imaging modality; improved; metabolomics; novel; novel diagnostics; prospective; screening; tool; treatment group; treatment response; tv watching

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.

我们的假设是高级磁共振成像（MRI）技术与 可以利用脑脊液（CSF）代谢物的定量评估来发展综合 用于评估疾病严重程度和晚期儿童治疗反应的生物标志物集 神经元粘膜脂肪促脂肪促（LINCL）。我们工作的最终目标是准确，客观地评估 治疗功效，从而改善了LINCL受试者的医疗管理，尤其是作为新的。 Lincl的治疗选择可用。我们的具体目标是开发成像生物标志物面板 用于评估Lincl疾病的严重程度和治疗反应 大脑，并将其与CSF代谢组学的结果进行比较。 我们的具体目的如下：目标1）开发大脑区域特异性磁共振成像 生物标志物面板，包括扩散系数，扩散分数各向异性，T2松弛时间，T2* 放松时间，CSF的体积百分比和质子光谱代谢物比率。我们将 在入学时检查对照组的16个lincl受试者中的30多个大脑区域，再次检查 18个月后。目标2：开发一个CSF代谢物生物标志物面板，其中包括评估 1000种化合物，并测试其与MRI生物标志物，疾病严重程度的临床指标和 主题年龄。 CSF将通过腰椎穿刺从对照组的16个lincl受试者中收集 在接受基因治疗前一天，在18个月后再次进行麻醉。 目标3：应用MRI生物标志物面板评估AAVRH的治疗功效。10介导 Lincl的基因治疗。治疗组中的16名受试者将在5 MRI时间点进行检查， 包括在筛查时，治疗前一天，在6、12和18 治疗后几个月。