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Novel Atomic Force Microscopy Based Biopanning for Isolation of Morphology Specific Reagents against TDP-43 Variants in Amyotrophic Lateral Sclerosis

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Published on: February 12, 2015

通过在CSF中中和具有播种能力的TDP-43来向肌缩性侧面硬化症

Mickael Audrain¹, Anne-Laure Egesipe¹, Noémie Tentillier¹

¹Research, AC Immune SA, 1015 Lausanne, Switzerland.

Brain communications

|November 29, 2023

概括

脑脊液 (CSF) 中43kDa (TDP-43) 种的病理性交换性反应DNA结合蛋白可能驱动肌缩侧面硬化症 (ALS) 的进展. 一种新的测试检测到这些种子,而单克隆抗体则在ALS患者的骨髓液中中和它们.

科学领域:

神经科学是一个神经科学.
生物化学生物化学
病理学病理学病理学

背景情况:

肌缩性侧面硬化症 (ALS) 的特征是43kDa (TDP-43) 聚合的异常交换反应DNA结合蛋白.
大脑脊髓液 (CSF) 中的病态TDP-43物种可能有助于疾病的传播和神经毒性.
这些物种可以充当种子,模拟生理TDP-43的聚合并传播病理.

研究的目的:

建立种子放大试验 (SAA) 以检测散发性ALS患者的CSF中的种植能力强的TDP-43物种.
开发一种测试方法,以确定中和这些病理性TDP-43物种所需的治疗性抗体度.
为了证明单克隆抗体 (ACI-5891.9) 在中和TDP-43种子中的有效性,在ALS患者中.

主要方法:

开发一种强大的种子放大试验 (SAA),以检测患者的脑脊髓炎中具有播种能力的TDP-43.
创建第二个试验,以测量用治疗性单克隆抗体中和TDP-43物种的目标参与.
单克隆抗体ACI-5891.9的药理动力学/药理动力学评估in vivo和in vitro以确定有效的CSF度.

主要成果:

与健康对照组相比,SAA检测到散性ALS患者的CSF基质聚合的显著加速.
确定ACI-5891.9的CSF度约为1100 ng/mL,足以维持持续的目标和.
在SAA中,ACI-5891.9有效地在ALS患者的CSF中中和了TDP-43病原性种子.

结论:

有证据支持TDP-43病理的通过CSF传播,这可能解释了ALS的非连续临床传播.
治疗性单克隆抗体ACI-5891.9显示,它能够在ALS患者中中和有毒的,细胞外播种有能力的TDP-43物种.
这项翻译性研究验证了TDP-43在CSF中的播种作为潜在的生物标志物和ALS的治疗标.

关键词:

这就是ALS.美国人美国人 RT-QuICIC 在TDP-43中使用.生物标志物生物标志物免疫疗法免疫疗法

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