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高剂量的系统性腺相关病毒载体的使用会导致肝脏和鼻状内皮细胞损伤

Juliette Hordeaux¹, R Jason Lamontagne¹, Chunjuan Song¹

¹Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

Molecular therapy : the journal of the American Society of Gene Therapy

|February 8, 2024

概括

在非人类灵长类动物中,高剂量腺相关病毒 (AAV) 给药导致肝毒性,包括血小板微血栓和鼻状损伤. 这种毒性似乎与高AAV剂量有关,而不是转基因,影响肝脏微血管.

科学领域:

* 基因治疗载体安全性
* 非人类灵长类动物毒理学模型
*肝脏微血管损伤 *肝脏微血管损伤

背景情况:

* 腺相关病毒 (AAV) 载体对基因疗法具有前景.
*高剂量全身AAV的使用需要进行彻底的毒理学评估.
*非人类灵长类动物是AAV载体安全研究的关键模型.

研究的目的:

* 调查非人类灵长类动物高剂量全身AAV的毒理概况.
* 描述观察到的毒性的性质和原因.
* 要区分转基因特异性毒性和AAV剂量依赖性影响.

主要方法:

*回顾性分析用于治疗性转基因的毒理学研究在Cynomolgus和 rhesus.
* 在 rhesus macaques 中对增强绿色光蛋白 (eGFP) -AAV 的前性研究.
*综合分析包括肝脏组织病理学,免疫组织学和单核RNA测序.

主要成果:

*高剂量的系统性AAV诱导了透氨炎,血小板狭窄和补体激活.
* 血小板缩与侧侧侧侧血小血小板缩和侧侧侧侧内皮损伤相关.
*在高剂量 (≥1 × 10^14 GC/kg) 的治疗转基因和eGFP中观察到类似的毒性.

结论:

*高剂量的全身AAV给药,而不是转基因表达,与非人类灵长类动物的急性肝毒性有关.
* AAV诱导的肝损伤涉及微血管损伤,特别是鼻状内皮损伤和血小板封存.
* 发现突出了高剂量静脉注射AAV影响肝脏微血管的潜在风险.

关键词:

在 AAV AAV AAV 中.国家卫生健康计划 (NHP)这就是TMAMA的意义.腺相关病毒的病毒.它们的内皮质 (endothelium).肝脏肝脏肝脏肝脏肝脏肝脏非人类灵长类的灵长类.血栓性微血管病变 - - 血栓性微血管病变毒性的毒性毒性的毒性

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