对基于AAV的基因治疗载体的先天性免疫反应:补充激活和细胞因子释放的机制
Rebecca Xicluna1, Petra C Schwalie1, Emma Bell1
1Roche Pharma Research and Early Development, Roche Innovation Center Basel, 4070 Basel, Switzerland.
Molecular therapy. Methods & clinical development
|September 8, 2025
概括
再组合腺相关病毒 (rAAV) 通过激活补充通路和释放炎症类细胞因子,触发免疫反应. 这种免疫激活受病毒囊类型,先前存在的抗体和载体基因组内容的影响.
科学领域:
- 免疫学 免疫学 免疫学
- 基因治疗 基因治疗
- 病毒学 病毒学
背景情况:
- 再组合腺相关病毒 (rAAV) 是体内基因传递的关键.
- 对rAAV的免疫反应限制了它们的临床疗效,并导致不良事件.
研究的目的:
- 为了研究先天免疫系统与rAAV.rAAV的相互作用.
- 评估rAAV暴露后的补充激活和细胞因子释放.
主要方法:
- 在20名健康捐献者身上进行了全血检测 (WBA).
- 在rAAV刺激后测量了补充激活和细胞因子释放.
- 转录学识别了响应的免疫细胞类型.
主要成果:
- AAV2和AAV8囊激活了补充,主要是通过古典途径,有时通过血清阴性捐赠者的替代途径.
- 观察到显著的细胞因子和化学因子释放,涉及单细胞,NK细胞,T细胞和B细胞.
- 与AAV8相比,AAV2诱导了更大的细胞因子释放,由先前存在的抗体增强;干扰素α释放取决于CpG含量.
结论:
- 对rAAV囊体和基因组的先天性和适应性免疫能激活补充和炎症介导体.
- 了解这些免疫相互作用对于安全有效的rAAV基因治疗至关重要.
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