Plasma neurofilament light chain as a potential disease monitoring biomarker in Wolfram syndrome

Wolfram综合征(OMIM#222300)是一种罕见的常染色体隐性遗传病，最常见的特征是 儿童期起病的胰岛素依赖型糖尿病、视神经萎缩、感音神经性耳聋和糖尿病 尿崩症。症状出现在儿童早期，并随着时间的推移而增加，最终导致失明， 在成年初期出现耳聋、共济失调和其他明显的神经系统症状。纵向分析表明 证明了特定的临床(例如视力、色觉)和衍生的神经成像变量(例如 丘脑和腹侧脑桥体积)随着时间的推移而恶化。这些措施现在正被用于正在进行的 临床疗效试验(ClinicalTrials.gov标识：NCT03717909)。然而，它们也是昂贵的，时间- 消耗和需要专门的现场设备和专业知识。相比之下，基于生物流体的测量方法 神经退行性变将更便宜，更容易标准化和可重复，因此对 正在进行的和未来的临床试验，旨在减缓或停止神经进展。新出现的生物流体标志物 神经退行性变，神经丝轻链(NFL)和胶质纤维酸性蛋白(GFAP)似乎敏感 但在神经退行性疾病中没有特异性。Wolfram患者血浆中NFL水平较高 与对照组比较，而GFAP在这种疾病中还没有研究。我们需要了解如果 NFL在Wolfram升高，独立于包括糖尿病状态和年龄在内的潜在混杂因素，无论其 水平会随着时间的推移而变化，以及这些变化是否会跟踪神经症状的进展。临床 验证NFL，可能还有GFAP，使用相同的分析方法在相同的血液样本中测量，是一种 建议在干预研究或实施中使用NFL和/或GFAP的重要先驱 动物模型的神经病理学验证研究。本提案的重点是以下这些必要的后续步骤 如果成功，将为使用NFL和/或GFAP监测神经变性提供一个强大的平台 沃尔夫拉姆综合征。

Wolfram syndrome (OMIM #222300) is a rare autosomal recessive disorder, characterized most frequently by childhood-onset insulin dependent diabetes, optic nerve atrophy, sensorineural hearing loss, and diabetes insipidus. Symptoms appear in early childhood and increase over time, ultimately resulting in blindness, deafness, ataxia and other significant neurologic symptoms by early adulthood. Longitudinal analyses have demonstrated that specific clinical (e.g. visual acuity, color vision) and derived neuroimaging variables (e.g. thalamic & ventral pons volumes) deteriorate over time. These measures are now being used in an ongoing clinical efficacy trial (ClinicalTrials.gov Identifier: NCT03717909). However, they are also costly, time- consuming and require specialized on-site equipment and expertise. In contrast, a biofluid-based measure of neurodegeneration would be cheaper, more easily standardized and repeatable, and thus extremely useful for ongoing and future clinical trials designed to slow or halt neurologic progression. Emerging biofluid markers of neurodegeneration, neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP), appear sensitive but non-specific in neurodegenerative diseases. NfL levels are greater in plasma of individuals with Wolfram syndrome compared to controls while GFAP has not been studied in this disease. We need to understand if NfL is elevated in Wolfram independent of potential confounders including diabetic status and age, whether its levels change over time and whether these changes track the progression of neurologic symptoms. Clinical validation of NfL, and possibly GFAP, measured in the same blood sample using the same assay, is an important precursor to proposing the use of NfL and/or GFAP in intervention studies or conducting neuropathological validation studies in animal models. This proposal is focused on these necessary next steps and, if successful, will provide a strong platform for using NfL and/or GFAP to monitor neurodegeneration in Wolfram syndrome.