复制缺陷的猿类腺病毒1载体在小鼠模型中的生物分布
Juan Chen1,2, Xiaojuan Guo1, Xiaohui Zou1
1NHC Key Laboratory of Medical Virology and Viral Diseases, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 100052, China.
Viruses
|April 27, 2024
概括
给药途径显著影响基因转移载体的疗效. simian adenovirus 1 载体的鼻内或肌内输送显示了疫苗开发的有希望的结果,具有重复管理的潜力.
科学领域:
- 基因治疗 基因治疗
- 病毒学 病毒学
- 免疫学 免疫学 免疫学
背景情况:
- 施用途径极大地影响基因转移载体的生物分布和转基因表达.
- Simian adenovirus 1 (SAdV-1) 载体正在被探索用于基因传递应用.
研究的目的:
- 在小鼠模型中研究携带记者基因 (露西法酶和GFP) 的新型SAdV-1载体的生物分布和表达.
- 评估不同给药途径 (静脉,胃内,鼻内,肌内) 对载体性能和免疫原性的影响.
- 评估重复的载体管理和不同腺病毒血清型的顺序使用的可行性.
主要方法:
- 构建一个SAdV-1载体 (SAdV1-GFluc) 编码火虫光酶和GFP.
- 使用生物发光成像和实时PCR进行病毒DNA跟踪的生物分布分析.
- 流细胞测量用于识别目标细胞.
- 评估中和抗体 (NAb) 标位.
- 免疫组织化学测定呼吸道中转化细胞.
主要成果:
- 静脉注射导致肝脏和脏的生物分布,向巨细胞和肝细胞.
- 由于诱导NAbs,重复的静脉注射是无效的.
- 胃内给药显示过渡性表达,允许重复剂量.
- 鼻内注射导致中度,持续的呼吸道表达,在重复剂量时,NAb增加最小.
- 肌肉内注射导致局部,持续的表达,但重复注射损害了疗效.
- 顺序给予SAdV-1和人类腺病毒5 (HAdV-5) 载体恢复了 luciferase 的活性.
结论:
- 在疫苗开发中,对于SAdV-1载体的传递,鼻内和肌内路线是首选的.
- 免疫反应,特别是NAbs,限制了相同载体血清型的重复注射.
- 不同腺病毒血清型的顺序管理提供了一种克服免疫局限性的策略.
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