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

基本信息

批准号：
10226346
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
项目类别：
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/10226346
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 juvenile neuronal ceroid lipofuscinosis 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

项目摘要

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.

项目概要神经元蜡质脂褐质沉积症 (NCL) 是一组神经发育疾病，分为以下几类：常染色体隐性遗传性溶酶体贮积症。临床特征包括视网膜病变、细胞内病变溶酶体蜡样质和脂褐素的积累、癫痫发作、运动能力下降和痴呆。 CLN3疾病（幼年神经元蜡质脂褐质沉着症，JNCL）是最常见的 NCL 类型之一，由 16号染色体上的CLN3基因突变。具有CLN3突变的个体表现出持续的下降儿童后期和早期的认知功能和言语智力能力青春期。这种下降的确切神经病理学基础尚未得到很好的理解和客观目前尚无疾病进展的神经生物标志物（神经标志物）。然而，我们的初步数据表明，跟踪疾病严重程度的 CLN3 疾病生物标志物的良好候选者可以是在听觉失配负性背景下使用高密度脑电图 (EEG) 进行识别实验。使用这些方法，我们能够显示 P1 成分的持续下降随着 CLN3 疾病严重程度的增加，听觉诱发反应。在这里，我们建议进一步加深对儿童和青少年听觉处理的理解 CLN3 疾病，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基因突变的 CLN3 疾病小鼠模型，以确定 CLN3 疾病共有的内表型患者和小鼠。我们还将测试自发荧光脂色素是否积累优先发生在中间神经元的特定子集中，并预测它们随后的损失以及剩余中间神经元肥大。这种三管齐下的技术和方法的融合这两个物种都有可能产生独特的机会来了解潜在的神经生理学 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 CLN3 疾病首先发生在小鼠身上，其次发生在患者身上。这种创新方法将患者捆绑在一起在该疾病的小鼠模型中进行相同测量的神经生理学标记将允许改善和更有效地开发新疗法的临床前，改进对疾病进展的测量临床试验以及这些进展改善了 CLN3 突变患者的预后。