Bridging the translational divide from cells to patients: toward reliable neuromarkers of Batten disease

弥合从细胞到患者的翻译鸿沟：寻找巴顿病的可靠神经标志物

• 批准号: 10085501
• 负责人: Kuan Hong Wang
• 金额: $ 27.46万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10085501
• 关键词: Attention; Auditory; Auditory Evoked Potentials; Auditory Perception; Auditory area; Biological Assay; Biological Markers; Blindness; CLN3 gene; Cells; Ceroid; Child; Childhood; Chromosome 16; Chronic; Clinical; Clinical Trials; DNA Sequence Alteration; Data; Dementia; Development; Disease; Disease Marker; Disease Progression; Disease model; Electroencephalography; Foundations; Frequencies; Future; Hearing Tests; Human; Hypertrophy; Impaired cognition; Individual; Intellectual and Developmental Disabilities Research Centers; Interneurons; Intervention; Lead; Lipofuscin; Measurement; Measures; Memory; Methods; Modeling; Motor; Mus; Mutation; Neurologic; Neuronal Ceroid-Lipofuscinosis; Neurons; Outcome Measure; Participant; Pathology; Patient-Focused Outcomes; Patients; Pattern; Persons; Positioning Attribute; Reporter; Reporting; Research Project Grants; Retinal Diseases; Seizures; Sensory; Severities; Severity of illness; Speech Perception; Spielmeyer-Vogt Disease; Staging; Techniques; Testing; Time; Transgenic Mice; Universities; Work; auditory processing; auditory stimulus; base; calcium indicator; cell type; cognitive function; density; design; early adolescence; effectiveness testing; endophenotype; excitatory neuron; experimental study; human disease; improved; improved outcome; in vivo two-photon imaging; inhibitory neuron; innovation; lipopigments; mouse model; neuromechanism; neuron loss; neurophysiology; novel therapeutics; patient/disease registry; pre-clinical; preclinical development; response; semantic processing; therapeutic effectiveness; therapeutic evaluation; young adult

PROJECT SUMMARY Neuronal Ceroid Lipofuscinoses (NCLs) are a group of neurodevelopmental diseases categorized as autosomal recessive lysosomal storage disorders. Clinical features include retinopathy, intracellular accumulation of lysosomal ceroid and lipofuscin, seizures, motor decline and dementia. CLN3 disease (Juvenile Neuronal Ceroid Lipofuscinosis, JNCL) is one of the most common types of NCL, and results from mutations in the CLN3 gene on chromosome 16. Individuals with the CLN3 mutation show a consistent decline in cognitive functioning and verbal intellectual abilities over the course of later childhood and early adolescence. The precise neuropathological bases of this decline are not yet well understood and objective neurologic biomarkers (neuromarkers) of disease progression are not currently available. Yet, our preliminary data indicate that a good candidate for a biomarker of CLN3 disease that tracks with disease severity can be identified using high-density electroencephalography (EEG) in the context of auditory mismatch negativity experiments. Using these methods we have been able to show consistent declines in the P1 component of the auditory evoked response as CLN3 disease severity increases. Here we propose to further develop our understanding of auditory processing in children and young adults with CLN3 disease with a focus on validating a biomarker of the disease. Simultaneously we propose to use a mouse model of CLN3 disease with the same genetic mutation to identify an endophenotype that is shared in both patients and mice. We will also test whether the accumulation of autofluorescent lipopigments preferentially occur in specific subsets of interneurons and predict their subsequent loss as well as the hypertrophy of remaining interneurons. This three-pronged, convergence of techniques and approaches in both species has the potential to yield unique opportunities to understand the underlying neurophysiology of CLN3 mutations and their impact on auditory processing, as well as encourage testing of future treatments for CLN3 disease first in mice and secondarily in patients. This innovative approach, tying the patient neurophysiological markers to identical measures in the murine model of the disease will permit improved and more efficient pre-clinical development of novel therapeutics, improved measurement of disease progression in clinical trials, and with these advances, lead to improved outcomes for patients with CLN3 mutations.

项目摘要 神经元粘脂蛋白（NCLS）是一组归类为归类为的神经发育疾病 常染色体隐性溶酶体储存障碍。临床特征包括视网膜病变，细胞内 溶酶体粘膜和脂肪霉素的积累，癫痫发作，运动衰落和痴呆。 CLN3病 （少年神经元cer脂性舒张病，JNCL）是最常见的NCL类型之一，是由 CLN3基因16染色体的突变。具有CLN3突变的个体显示出一致下降 在童年和早期的认知功能和言语智力能力中 青春期。这种下降的确切神经病理基础尚未得到充分理解和客观 目前尚无疾病进展的神经系统生物标志物（神经标志物）。但是，我们的初步 数据表明，可以追踪患有疾病严重程度的CLN3疾病生物标志物的好候选者 在听觉不匹配的背景下，使用高密度脑电图（EEG）确定 实验。使用这些方法，我们能够显示出在P1组件中的一致下降 随着CLN3疾病严重程度的增加，听觉引起了反应。 在这里，我们建议进一步发展我们对儿童和年轻人的听觉处理的理解 与CLN3疾病有关，重点是验证该疾病的生物标志物。同时我们建议使用 具有相同遗传突变的CLN3疾病的小鼠模型，以鉴定出共享的内表型 患者和小鼠。我们还将测试自动荧光脂质的积累 优先发生在中间神经元的特定子集中，并预测其随后的损失以及 剩余中间神经元的肥大。这种三管齐下的技术和方法的融合 这两种物种都有可能产生独特的机会，以了解 CLN3突变及其对听觉处理的影响，并鼓励测试未来的治疗方法 首先，小鼠的CLN3疾病，其次是患者。这种创新的方法，将患者绑定 在该疾病的鼠模型中，神经生理标志物是相同措施的相同措施，将允许改善，并且 新型治疗剂的更有效的临床前开发，改善了疾病进展的测量 临床试验以及这些进展，可改善CLN3突变患者的结局。