细胞应激和凝血因子的产生:当更多并不一定是更好的
Zhouji Chen1, Roland W Herzog2, Randal J Kaufman1
1Degenerative Diseases Program, Center for Genetic Diseases and Aging Research, SBP Medical Discovery Institute, California, USA.
Journal of thrombosis and haemostasis : JTH
|October 15, 2023
概括
血友病A (HA) 的基因疗法显示出希望,但面临挑战. 目前的方法与肝细胞中的第八因子 (FVIII) 分泌有困难,可能导致安全问题,并限制治疗的耐用性.
科学领域:
- 血液学 血液学 血液学
- 基因治疗 基因治疗
- 分子生物学分子生物学
背景情况:
- 血友病A (HA) 和B (HB) 治疗从血衍生因素演变为重组蛋白和基因疗法.
- 基因相关病毒载体 (AAV) 基因疗法已被批准用于HA和HB,但耐用性和安全性令人担忧.
研究的目的:
- 审查目前对限制肝细胞分泌第八因子 (FVIII) 的因素的理解.
- 探索FVIII在肝细胞表达的潜在病理生理后果.
主要方法:
- 关于血友病A,FVIII蛋白,基因疗法和肝细胞生物学的科学文献的综述.
- 分析与FVIII蛋白折叠,分泌和细胞应激反应相关的挑战.
主要成果:
- 与FIX不同的是,FVIII是一种大型蛋白质,容易发生错折和分泌不良.
- 在基因治疗中使用的B域删除的FVIII也表现出低效的分泌,并可以触发未折叠的蛋白质反应.
- 肝细胞中未折叠的蛋白质反应激活带来风险,包括功能受损,生存和潜在的瘤发生.
结论:
- 低效的FVIII分泌和相关的细胞压力是有效的HA基因治疗的主要障碍.
- 需要进一步的研究来克服FVIII分泌的限制,并确保血友病A的基因治疗的安全性和耐用性.
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