TDP-43 Proteinopathy in ALS-FTD: Mechanism, Target Validation and Biomarker

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阐明疾病机制，确定 研究人员正在为新的AAV9基因治疗提供一个治疗窗口，并开发ALS的预后测试。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C9ORF72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 机械的洞察力我们假设有可能发展一种前驱期的预后测试 ALS，这是在疾病最早期招募患者相关领域的一个关键未满足需求， 用于监测临床试验中的目标参与。最后，新出现的证据支持这样的观点，即TDP的损失- 43剪接阻遏影响许多关键途径。与针对ALS的这些途径中的每一个相反， 我们推测，通过靶向TDP-43剪接抑制机制，可能提供 如果这种治疗策略可以在可以确定的早期疾病期间提供， 使用这种新的TDP-43 "隐蔽"肽的诊断测定。正如我们之前所展示的，我们的AAV9-CTR具有 补充ALS中TDP-43功能丧失的潜力，我们假设， 这种基因治疗可以在我们的脊髓运动神经元中缺乏TDP-43的小鼠模型中定义。共同取得成果 将对理解疾病机制、验证 治疗策略和开发ALS前驱期的预后测试。

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 clarify disease mechanism, determine a therapeutic window for a novel AAV9 gene therapy, and develop a prognostic 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. We hypothesize that it would be possible to develop a prognostic 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. Finally, emerging evidence support the idea that loss of TDP- 43 splicing repression impact on many critical pathways. In contrast to targeting each of these pathways for ALS, we hypothesize that by targeting the mechanism of TDP-43 splicing repression, it may be possible to provide benefit to patients if such therapeutic strategy can be delivered during early disease which can be determined using this new diagnostic assay of TDP-43 “cryptic” peptide. As we showed previously that our AAV9-CTR has the potential to complement the loss of TDP-43 function in ALS, we hypothesize that a window of opportunity for this gene therapy can be defined in our mouse model lacking TDP-43 in spinal motor neurons. Together, results from our proposed studies will have important implications for understanding disease mechanism, validating therapeutic strategy and developing a prognostic test for the prodromal phase of ALS.