Targeting amyotrophic lateral sclerosis by neutralizing seeding-competent TDP-43 in cerebrospinal fluid

Mickael Audrain, Anne-Laure Egesipe, Noémie Tentillier, Laure Font, Monisha Ratnam, Lorene Mottier, Mathieu Clavel, Morgan Le Roux-Bourdieu, Alexis Fenyi, Romain Ollier, Elodie Chevalier, Florence Guilhot, Aline Fuchs, Kasia Piorkowska, Becky Carlyle, Steven E Arnold, James D Berry, Ruth Luthi-Carter, Oskar Adolfsson, Andrea Pfeifer, Marie Kosco-Vilbois, Tamara Seredenina, Tariq Afroz
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Abstract

Abstract In amyotrophic lateral sclerosis, a disease driven by abnormal transactive response DNA-binding protein of 43 kDa aggregation, CSF may contain pathological species of transactive response DNA-binding protein of 43 kDa contributing to propagation of pathology and neuronal toxicity. These species, released in part by degenerating neurons, would act as a template for aggregation of physiological protein contributing to the spread of pathology in the brain and spinal cord. In this study, a robust seed amplification assay was established to assess the presence of seeding-competent transactive response DNA-binding protein of 43 kDa species in CSF of apparently sporadic amyotrophic lateral sclerosis patients. These samples resulted in a significant acceleration of substrate aggregation differentiating the kinetics from healthy controls. In parallel, a second assay was developed to determine the level of target engagement that would be necessary to neutralize such species in human CSF by a therapeutic monoclonal antibody targeting transactive response DNA-binding protein of 43 kDa. For this, evaluation of pharmacokinetics/pharmacodynamic effect for monoclonal antibody, ACI-5891.9 in vivo and in vitro confirmed that a CSF concentration of ≈ 1100 ng/mL would be sufficient for sustained target saturation. Using this concentration in the seed amplification assay, ACI-5891.9 was able to neutralize the transactive response DNA-binding protein of 43 kDa pathogenic seeds derived from amyotrophic lateral sclerosis patient CSF. This translational work adds to the evidence of transmission of transactive response DNA-binding protein of 43 kDa pathology via CSF that could contribute to the non-contiguous pattern of clinical manifestations observed in amyotrophic lateral sclerosis and demonstrates the ability of a therapeutic monoclonal antibody to neutralize the toxic, extracellular seeding-competent transactive response DNA-binding protein of 43 kDa species in the CSF of apparently sporadic amyotrophic lateral sclerosis patients.
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通过中和脑脊液中具有种子能力的TDP-43靶向肌萎缩性侧索硬化
摘要肌萎缩性侧索硬化症是一种由43 kDa交互反应dna结合蛋白异常聚集引起的疾病,脑脊液中可能含有43 kDa交互反应dna结合蛋白的病理种,参与病理增殖和神经元毒性。这些物质部分是由退化的神经元释放出来的,它们将作为生理蛋白质聚集的模板,促进大脑和脊髓的病理扩散。在这项研究中,建立了一个强大的种子扩增试验,以评估在散发性肌萎缩性侧索硬化症患者脑脊液中是否存在43 kDa种的具有种子能力的交互反应dna结合蛋白。这些样品导致底物聚集的显著加速,将动力学与健康对照区分开来。与此同时,研究人员开发了第二种检测方法,以确定通过靶向43 kDa的交互反应dna结合蛋白的治疗性单克隆抗体来中和人脑脊液中这些物种所必需的靶标接合水平。为此,对单克隆抗体ACI-5891.9的体内和体外药代动力学/药效学效应进行评价,证实脑脊液浓度≈1100 ng/mL足以维持靶点饱和。在种子扩增实验中使用该浓度,ACI-5891.9能够中和来自肌萎缩侧索硬化症患者CSF的43 kDa致病种子的交互反应dna结合蛋白。这项翻译工作进一步证明了43 kDa病理的交互反应dna结合蛋白通过脑脊液传播,这可能有助于在肌萎缩侧索硬化症中观察到的非连续临床表现模式,并证明了治疗性单克隆抗体能够中和毒性。散发性肌萎缩性侧索硬化症患者脑脊液中43 kDa种的细胞外播种权交换反应dna结合蛋白。
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