肝细胞癌
内质网
病毒载体
背景(考古学)
癌症研究
肝细胞
生物
异位表达
凝血因子
基因
细胞生物学
医学
重组DNA
内科学
遗传学
体外
古生物学
作者
Audrey Kapelanski-Lamoureux,Zhouji Chen,Zu–Hua Gao,Ruishu Deng,Anthoula Lazaris,Cynthia Lebeaupin,Lisa Giles,Jyoti Malhotra,Jing Yong,Congming Zou,Ype P. de Jong,Peter Metrakos,Roland W. Herzog,Randal J. Kaufman
标识
DOI:10.1016/j.ymthe.2022.10.004
摘要
Hemophilia A gene therapy targets hepatocytes to express B domain deleted (BDD) clotting factor VIII (FVIII) to permit viral encapsidation. Since BDD is prone to misfolding in the endoplasmic reticulum (ER) and ER protein misfolding in hepatocytes followed by high-fat diet (HFD) can cause hepatocellular carcinoma (HCC), we studied how FVIII misfolding impacts HCC development using hepatocyte DNA delivery to express three proteins from the same parental vector: (1) well-folded cytosolic dihydrofolate reductase (DHFR); (2) BDD-FVIII, which is prone to misfolding in the ER; and (3) N6-FVIII, which folds more efficiently than BDD-FVIII. One week after DNA delivery, when FVIII expression was undetectable, mice were fed HFD for 65 weeks. Remarkably, all mice that received BDD-FVIII vector developed liver tumors, whereas only 58% of mice that received N6 and no mice that received DHFR vector developed liver tumors, suggesting that the degree of protein misfolding in the ER increases predisposition to HCC in the context of an HFD and in the absence of viral transduction. Our findings raise concerns of ectopic BDD-FVIII expression in hepatocytes in the clinic, which poses risks independent of viral vector integration. Limited expression per hepatocyte and/or use of proteins that avoid misfolding may enhance safety.
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