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

肌萎缩性侧索硬化症（ALS），一种疾病，其中过早丧失上，下运动神经元导致 致命性瘫痪，越来越多地认识到有临床，遗传和病理重叠，额颞叶 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）被鉴定为 在ALS和FTLD患者中均观察到泛素化胞质包涵体， 基因TARDBP随后被鉴定为ALS的主要原因。ALS是最常见的运动神经元 老年痴呆症是成年人中最常见的疾病，FTLD是60岁以下最常见的痴呆症。然而，没有有效的 这些神经退行性疾病的治疗和管理集中在治疗症状和 提供姑息治疗，以改善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发展的早期阶段。但我们 我相信它们具有巨大的潜力，因为它们对潜在疾病生物学的直接影响， 延缓疾病进展的潜力。天然存在的人单克隆抗体代表了新的 用于包括ALS的神经系统疾病的治疗分子。据推测，人类自身抗体 靶向错误折叠的致病蛋白质，如TDP-43，作为监视分子，以消除有毒物质， 在它们引起有害反应之前聚集。这种抗体可能会中和 寡聚体和/或通过小胶质细胞摄取促进沉积的聚集体的清除。嵌合或人源化 抗体可引发不良免疫反应，导致严重的副作用，甚至死亡， 由于被人免疫系统中和，治疗性抗体的效力降低。回收自身抗体 来自没有衰弱状况的个体的抗体具有更高的安全性，因为该抗体已被证明具有耐受性 在人体内。结合人类免疫系统典型的杰出亲和力成熟， 这些抗体可能提供优于非人源抗体的上级治疗窗口。 开发针对ALS和FTLD的有效疗法的瓶颈是缺乏具有以下特征的模型： 病理学特征与患者大脑中存在的病理学特征非常相似。我们最近的工作建立了新的 TDP-43聚集的细胞模型，通过引入直接从患者中提取的病理形式 通过一种机制，导致病理在细胞系和人类神经元中的积累和传播 模拟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。我们的策略是识别患者的自然发生 靶向病理形式TDP-43的保护性自身抗体，并继续进行它们各自的研究。 用于ALS和FTLD治疗用途的克隆、表征和开发。

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.