纵向动力学AAV5矢量集成配置文件和评价的克隆扩张在小鼠的纵向动力学
Ashrafali Mohamed Ismail1, Evan Witt1, Taren Bouwman1
1BioMarin Pharmaceutical Inc., Novato, CA 94949, USA.
Molecular therapy. Methods & clinical development
|August 6, 2024
概括
腺相关病毒 (AAV) 基因疗法载体主要保持为插曲,罕见,稳定整合. 这项研究在小鼠模型中没有发现来自AAV5矢量集成的瘤发生或纤维化的证据.
科学领域:
- 分子生物学分子生物学
- 基因治疗 基因治疗
- 病毒学 病毒学
背景情况:
- 基因转移中广泛使用的基因相关病毒 (AAV) 基因载体,主要以异染色体发作形式持续存在.
- 一小部分AAV载体基因组可以整合到宿主基因组中,这引发了对依赖载体调节元素的瘤发生的理论担忧.
研究的目的:
- 为了研究腺相关病毒血清型5 (AAV5) 载体的整合概况.
- 评估使用Sf和HEK293细胞生成的AAV载体的安全性和整合特性,模仿血友病A基因治疗的valoctocogene roxaparvovec.
主要方法:
- 用小鼠模型分析了AAV5矢量的集成概况.
- 综合频率,时间,分布和与基因表达和宿主细胞增殖的关联被使用深度测序来评估.
主要成果:
- 大多数载体基因组 (95%) 是环节性,在Sf和HEK293产生的载体中观察到的集成频率低 (1.792.70集成/1,000个细胞).
- 整合发生迅速 (在1周内),保持稳定,多克隆,随机分布,并显示在高度表达的肝脏基因转录起点附近的丰富.
- 没有检测到载体生产平台的差异,克隆扩张,瘤发生或纤维化.
结论:
- AAV5 矢量集成发生在低频率,随着时间的推移是稳定的,并且似乎与瘤发生或纤维化等不良事件无关.
- 这些发现通过表征载体基因组整合模式,支持基于AAV5的基因疗法的安全性,包括valoctocogene roxaparvovec.
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