Development of immunotherapy targeting pathological TDP-43 in ALS and FTLD

肌萎缩侧索硬化症(ALS)是一种上下运动神经元过早丧失导致的疾病 到致命性瘫痪，越来越被认为与额颞部有临床、遗传和病理上的重叠。 脑叶变性(FTLD)，一种以行为和语言为特征的神经退行性疾病 功能障碍。2006年，TAR DNA结合蛋白43(TDP-43)被确定为 在ALS和FTLD患者中观察到泛素化的细胞质内含物和 TARDBP基因随后被确定为ALS的主要原因。肌萎缩侧索硬化症是最常见的运动神经元 成年人的疾病和FTLD是60岁以下最常见的痴呆症。然而，目前还没有有效的方法 这些神经退行性疾病的治疗和管理侧重于治疗症状和 提供姑息治疗，以提高这些患者的生活质量。 针对神经退行性疾病的免疫疗法仍处于早期开发阶段。然而，我们 相信它们具有巨大的潜力，因为它们对潜在的疾病生物学和他们的 有可能延缓疾病的进展。自然产生的人类单抗代表了新的 治疗包括肌萎缩侧索硬化症在内的神经系统疾病的分子。据推测，人类自身抗体 靶向错误折叠的致病蛋白，如TDP-43，作为监测分子来消除有毒物质 在它们可能引发有害反应之前进行聚合。这种抗体可能会中和血管活性。 低聚物和/或通过小胶质细胞摄取促进沉积聚集体的清除。嵌合体或人性化 抗体可引起不良免疫反应，导致严重的副作用，甚至死亡，并减少 由于被人体免疫系统中和而产生的治疗性抗体的疗效。检索到的自身抗体 来自没有衰弱条件的个体的抗体具有更高的安全性，因为已证明抗体具有耐受性。 在人体内。结合人类免疫系统典型的出色亲和力成熟， 这些抗体可能提供比非人类来源的抗体更好的治疗窗口。 开发有效的治疗ALS和FTLD的一个瓶颈是缺乏 病理特征与患者大脑中存在的特征非常相似。我们最近的工作建立了新的 通过引入直接从患者身上提取的病理形式建立TDP-43聚集的细胞模型 大脑，通过一种机制，导致病理在细胞系和人类神经元中积累和传播 模仿导致疾病进展的分子事件。在这个项目中，我们将利用这些 开发TDP-43免疫疗法的工具。我们的策略是识别自然发生的患者 针对TDP-43病理形态的保护性自身抗体及其各自的研究进展 肌萎缩侧索硬化症和腰椎间盘突出症治疗用药的克隆、鉴定和开发。

Amyotrophic lateral sclerosis (ALS), a disease in which premature loss of upper and lower motor neurons leads to fatal paralysis, is increasingly recognized to have clinical, genetic and pathological overlap with frontotemporal lobar degeneration (FTLD), a neurodegenerative disorder characterized by behavioral and language dysfunction. In 2006, TAR DNA-binding protein 43 (TDP-43) was identified as the major component of ubiquitinated cytoplasmic inclusions observed in both ALS and FTLD patients and dominant mutations in the gene TARDBP were subsequently identified as a primary cause of ALS. ALS is the most common motor neuron disease in adults and FTLD the most common dementia under the age of 60. Nevertheless, there are no effective therapies for these neurodegenerative disorders and management focuses on treating the symptoms and providing palliative care in order to improve the quality of life of these patients. Immunotherapies against neurodegenerative diseases are still at their early stages of development. Yet, we believe that they hold tremendous potential due to their direct impact on the underlying disease biology and their potential to delay disease progression. Naturally occurring human monoclonal antibodies represent novel therapeutic molecules for neurologic disorders including ALS. It is postulated that human autoantibodies targeting misfolded pathogenic proteins, such as TDP-43, serve as surveillance molecules to eliminate toxic aggregates before they can elicit a deleterious response. Such antibodies might neutralize the activity of oligomers and/or facilitate clearance of deposited aggregates via microglia uptake. Chimeric or humanized antibodies can elicit an adverse immune response, resulting in severe side-effects, even death, and reduced efficacy of the therapeutic antibody due to neutralization by the human immune system. Autoantibodies retrieved from individuals with no debilitating conditions have a higher safety profile, as the antibody has proven tolerability in the human body. Combined with the outstanding affinity maturation typical of the human immune system, those antibodies are likely to offer a therapeutic window superior to antibodies of non-human origin. A bottleneck in the development of effective therapies against ALS and FTLD is the lack of models with pathological features faithfully resembling those present in patient brains. Our recent work has established new cellular models of TDP-43 aggregation, via the introduction of pathological forms extracted directly from patient brains, leading to accumulation and propagation of pathology in cell lines and human neurons via a mechanism mimicking the molecular events leading to disease progression. In this project, we will capitalize on these tools to develop TDP-43 immunotherapy. Our strategy is to identify patients with naturally occurring protective autoantibodies targeting pathological forms of TDP-43 and to proceed with their respective cloning, characterization and development for therapeutic use in ALS and FTLD.