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

项目摘要 神经元蜡样脂褐质病（NCL）是一组神经发育疾病，分类为 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 溶酶体蜡样物质和脂褐质的积累、癫痫、运动衰退和痴呆。CLN3病 青少年神经元蜡样脂褐质沉积症（Juvenile Neuronal Ceroid Lipofuscinosis，JNCL）是最常见的NCL类型之一， 16号染色体上的CLN3基因突变。CLN3突变的个体表现出一致的下降， 在儿童后期和早期的认知功能和语言智力能力方面， 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 疾病进展的神经学生物标志物（神经标志物）目前不可用。然而，我们初步的 数据表明，追踪疾病严重程度的CLN3疾病生物标志物的良好候选物可以是 使用高密度脑电图（EEG）在听觉不匹配负性的背景下识别 实验使用这些方法，我们已经能够显示在P1分量的一致下降， 听觉诱发反应随着CLN3疾病严重程度的增加而增加。 在这里，我们建议进一步发展我们对儿童和年轻人听觉处理的理解 与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 具有相同遗传突变的CLN3疾病的小鼠模型，以鉴定在CLN3疾病中共享的内表型。 患者和小鼠。我们还将检测自发荧光脂色素的积累是否 优先发生在特定的中间神经元亚群，并预测其随后的损失以及 剩余的中间神经元肥大。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，以了解潜在的神经生理学， CLN3突变及其对听觉处理的影响，以及鼓励未来治疗的测试， CLN3疾病首先在小鼠中，其次在患者中。这种创新的方法， 神经生理学标记物与疾病的鼠模型中的相同测量值的比较将允许改善和 新疗法的临床前开发更有效， 临床试验，并与这些进展，导致改善的结果与CLN3突变的患者。

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.