在C9orf72相关的ALS中,抗意义寡核酸治疗的分子影响
Zachary T McEachin1, Mingee Chung2, Sabrina A Stratton2
1Department of Human Genetics, Emory University, Atlanta, GA 30322, USA; Department of Cell Biology, Emory University, Atlanta, GA 30322, USA; Laboratory for Translational Cell Biology, Emory University, Atlanta, GA 30322, USA; Goizueta Brain Health Institute Center for Neurodegenerative Diseases, Emory University, Atlanta, GA 30322, USA.
Cell
|August 27, 2025
概括
针对C9orf72相关的ALS的抗意义寡核酸BIIB078显示广泛分布,但未能影响关键的中枢神经系统病理. 在ASO治疗中需要进一步研究有效的药理动力学生物标志物.
科学领域:
- 神经科学
- 遗传学
- 药理学
背景情况:
- 与C9orf72相关的ALS源于G4C2重复扩张,产生有毒的RNA和二重复蛋白 (DPR).
- 由于缺乏临床益处,针对这些转录的抗意义寡核酸 (ASO) BIIB078 的临床试验被中止.
研究的目的:
- 评估BIIB078的中枢神经系统 (CNS) 目标参与.
- 在治疗后确定大脑脊髓液 (CSF) 的药理学生物标志物.
主要方法:
- 对接受BIIB078治疗的患者的脑脊髓液和中枢神经系统组织的分析.
- 对DPR,化TDP-43和蛋白质组的量化.
- 炎症生物标志物和RNase T2丰度的测量.
主要成果:
- 在脑脊液中减少了DPR和增加了炎症生物标志物 (CCL26).
- 在中枢神经系统组织中广泛分布的BIIB078,但持久的DPR和pTDP-43.
- 脊髓蛋白质特征没有显著变化,除了与BIIB078水平相关的RNase T2增加.
结论:
- BIIB078在c9ALS中对核心中枢神经系统病理的影响有限.
- 这项研究强调了对反映神经病理变化的药理学生物标志物的关键需求,以评估ASO的疗效.
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