A diagnostic biomarker for amyotrophic lateral sclerosis

肌萎缩性侧索硬化症（ALS）是一种以选择性肌萎缩性侧索硬化为特征的致死性成人发病运动神经元疾病。 上、下运动神经元的丧失，以及额颞叶痴呆（FTD），一种常见的痴呆形式 以行为、性格和/或语言逐渐恶化为特征的， 江西篇章转录激活反应元件DNA结合蛋白43（TDP-43）的神经病理学研究 发生在几乎所有ALS病例和大部分FTD病例中，神经退行性疾病目前没有 有效的治疗。该提案的总体目标是开发ALS的诊断测试。发展中 设计识别隐蔽外显子编码肽单克隆抗体，我们显示TDP-43的丢失 剪接抑制发生在症状前的C9 ORF 72患者中。这一新颖的发现支持了这样一种观点， TDP-43功能的丧失发生在疾病的早期阶段。在这个应用程序中，我们将建立这个重要的 机制的洞察力，并开发一种诊断测试的前驱阶段的ALS，一个关键的未满足的需要，在该领域 与在疾病的最早阶段招募患者以及监测靶点参与相关 临床试验这项应用中的拟议研究将对开发诊断测试具有重要意义 肌萎缩侧索硬化症的前驱期

Amyotrophic Lateral Sclerosis (ALS), a fatal adult onset motor neuron disease characterized by selective loss of upper and lower motor neurons, and Fronto-Temporal Dementia (FTD), a common form of dementia characterized by a progressive deterioration in behaviour, personality and/or language, share a common disease spectrum. The neuropathology involving Transactivation response element DNA-binding protein 43 (TDP-43) occurs in nearly all cases of ALS and large proportion of FTD, neurodegenerative diseases currently without effective therapy. The overarching goals of this proposal are to develop a diagnostic test for ALS. By developing monoclonal antibodies designed to recognize cryptic exon encode peptides, we show that loss of TDP-43 splicing repression occurs in pre-symptomatic C9ORF72 patients. This novel finding would support the idea that loss of TDP-43 function occurs during early stage of disease. In this application, we will establish this important mechanistic insight and develop a diagnostic test for prodromal phase of ALS, a critical unmet need in the field relevant for recruitment of patients at their earliest stage of disease and for monitoring target engagement in clinical trials. Proposed studies in this application will have important implications for developing a diagnostic test for the prodromal phase of ALS.