Afroz Tariq, Chevalier Elodie, Audrain Mickael, Dumayne Christopher, Ziehm Tamar, Moser Roger, Egesipe Anne-Laure, Mottier Lorène, Ratnam Monisha, Neumann Manuela, Havas Daniel, Ollier Romain, Piorkowska Kasia, Chauhan Mayank, Silva Alberto B, Thapa Samjhana, Stöhr Jan, Bavdek Andrej, Eligert Valerie, Adolfsson Oskar, Nelson Peter T, Porta Sílvia, Lee Virginia M-Y, Pfeifer Andrea, Kosco-Vilbois Marie, Seredenina Tamara
AC Immune SA, Lausanne, Switzerland.
AC Immune SA, Lausanne, Switzerland.
Neurobiol Dis. 2023 Apr;179:106050. doi: 10.1016/j.nbd.2023.106050. Epub 2023 Feb 20.
Effective therapies are urgently needed to safely target TDP-43 pathology as it is closely associated with the onset and development of devastating diseases such as frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) and amyotrophic lateral sclerosis (ALS). In addition, TDP-43 pathology is present as a co-pathology in other neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. Our approach is to develop a TDP-43-specific immunotherapy that exploits Fc gamma-mediated removal mechanisms to limit neuronal damage while maintaining physiological TDP-43 function. Thus, using both in vitro mechanistic studies in conjunction with the rNLS8 and CamKIIa inoculation mouse models of TDP-43 proteinopathy, we identified the key targeting domain in TDP-43 to accomplish these therapeutic objectives. Targeting the C-terminal domain of TDP-43 but not the RNA recognition motifs (RRM) reduces TDP-43 pathology and avoids neuronal loss in vivo. We demonstrate that this rescue is dependent on Fc receptor-mediated immune complex uptake by microglia. Furthermore, monoclonal antibody (mAb) treatment enhances phagocytic capacity of ALS patient-derived microglia, providing a mechanism to restore the compromised phagocytic function in ALS and FTD patients. Importantly, these beneficial effects are achieved while preserving physiological TDP-43 activity. Our findings demonstrate that a mAb targeting the C-terminal domain of TDP-43 limits pathology and neurotoxicity, enabling clearance of misfolded TDP-43 through microglia engagement, and supporting the clinical strategy to target TDP-43 by immunotherapy. SIGNIFICANCE STATEMENT: TDP-43 pathology is associated with various devastating neurodegenerative disorders with high unmet medical needs such as frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS) and Alzheimer's disease. Thus, safely and effectively targeting pathological TDP-43 represents a key paradigm for biotechnical research as currently there is little in clinical development. After years of research, we have determined that targeting the C-terminal domain of TDP-43 rescues multiple patho-mechanisms involved in disease progression in two animal models of FTD/ALS. In parallel, importantly, our studies establish that this approach does not alter the physiological functions of this ubiquitously expressed and indispensable protein. Together, our findings substantially contribute to the understanding of TDP-43 pathobiology and support the prioritization for clinical testing of immunotherapy approaches targeting TDP-43.
由于TDP-43病理学与诸如伴有TDP-43病理学的额颞叶痴呆（FTLD-TDP）和肌萎缩侧索硬化症（ALS）等毁灭性疾病的发生和发展密切相关，因此迫切需要有效的疗法来安全地靶向TDP-43病理学。此外，TDP-43病理学在诸如阿尔茨海默病和帕金森病等其他神经退行性疾病中作为一种共病理学存在。我们的方法是开发一种TDP-43特异性免疫疗法，该疗法利用Fcγ介导的清除机制来限制神经元损伤，同时维持TDP-43的生理功能。因此，通过结合体外机制研究以及TDP-43蛋白病的rNLS8和CaMKIIa接种小鼠模型，我们确定了TDP-43中的关键靶向结构域以实现这些治疗目标。靶向TDP-43的C末端结构域而非RNA识别基序（RRM）可减少TDP-43病理学并避免体内神经元丢失。我们证明这种挽救依赖于小胶质细胞对Fc受体介导的免疫复合物的摄取。此外，单克隆抗体（mAb）治疗增强了ALS患者来源的小胶质细胞的吞噬能力，为恢复ALS和FTD患者受损的吞噬功能提供了一种机制。重要的是，在保留TDP-43生理活性的同时实现了这些有益效果。我们的研究结果表明，靶向TDP-43 C末端结构域的单克隆抗体可限制病理学和神经毒性，通过小胶质细胞参与实现错误折叠的TDP-43的清除，并支持通过免疫疗法靶向TDP-43的临床策略。意义声明：TDP-43病理学与各种具有高度未满足医疗需求的毁灭性神经退行性疾病相关，如额颞叶痴呆（FTD）、肌萎缩侧索硬化症（ALS）和阿尔茨海默病。因此，安全有效地靶向病理性TDP-43是生物技术研究的关键范例，因为目前临床开发中几乎没有相关研究。经过多年研究，我们确定靶向TDP-43的C末端结构域可挽救FTD/ALS两种动物模型中疾病进展所涉及的多种病理机制。同时，重要的是，我们的研究表明这种方法不会改变这种普遍表达且不可或缺的蛋白质的生理功能。总之，我们的研究结果极大地有助于理解TDP-43病理生物学，并支持对靶向TDP-43的免疫疗法进行临床测试的优先级排序。
