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通过AAV恢复TDP-43功能而赋予的大脑广泛的生物分布缓解了前性痴呆症样缺陷

Tianyu Cao¹, Rashmi Thapa², Rongsong Liu³

¹Department of Pathology, The Johns Hopkins University School of Medicine.

bioRxiv : the preprint server for biology

|September 15, 2025

概括

使用穿透血脑屏障的AAV载体的基因疗法在TDP-43病理 (FTLD-TDP) 的前叶退化小鼠模型中成功恢复了TDP-43功能,显示出有前途的治疗潜力.

科学领域:

神经科学是一个神经科学.
遗传学是一个遗传学.
分子生物学分子生物学

背景情况:

TDP-43蛋白质功能障碍是TDP-43病理 (FTLD-TDP) 的前叶退化的一个关键因素.
目前对FTLD-TDP缺乏治疗方法,需要新的治疗策略.
模仿早期FTLD-TDP阶段的小鼠模型对于开发有效干预至关重要.

研究的目的:

评估血液-大脑屏障 (BBB) 透性腺相关病毒 (AAV-PHP.eB) 在传递治疗基因以恢复 TDP-43 功能的有效性.
评估AAV-PHP.eB介导基因治疗在小鼠模型中改善FTLD-TDP类表型的潜力.

主要方法:

为了大脑的广泛生物分布,使用了BBB-透的AAV向量 (AAV-PHP.eB).
在TDP-43缺陷的小鼠模型 (CamKIIa-CreER;Tardbp) 中通过脑内内注射携带剪接抑制剂 (CTR) 的AAV-PHP.eB.
评估TDP-43治疗后的功能恢复,神经元活动,记忆和神经元损失.

主要成果:

AAV-PHP.eB成功地将CTR传递给成人海马神经元.
使用AAV-PHP.eB-CTR的基因治疗恢复了TDP-43功能,减少了异常的神经元活动,并改善了记忆缺陷.
治疗挽救了神经元的损失,并且在老年小鼠中表现出良好的安全性,没有观察到任何不良影响.

结论:

BBB交叉的AAV载体可以有效地为FTLD-TDP向成年大脑传递治疗基因.
通过AAV-PHP.eB介导的CTR基因疗法显示出治疗FTLD-TDP的前景,需要进行临床研究.

关键词:

在 AAV AAV AAV 中.在AD-TDP的基础上.这是一个FTLD-TDP.迟到了迟到了在 TDP-43 功能障碍中.生物分销生物分销一个神秘的前子.前脑神经元前脑神经元基因治疗的基因疗法过度活跃症是一种过度活跃.记忆力缺陷记忆力缺陷鼠标模型鼠标模型鼠标模型拼接压缩机压缩机的拼接

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