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• W4306173791 startingPage "3542" @default.
• W4306173791 abstract "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." @default.
• W4306173791 created "2022-10-14" @default.
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• W4306173791 date "2022-12-01" @default.
• W4306173791 modified "2023-10-18" @default.
• W4306173791 title "Ectopic clotting factor VIII expression and misfolding in hepatocytes as a cause for hepatocellular carcinoma" @default.
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• W4306173791 doi "https://doi.org/10.1016/j.ymthe.2022.10.004" @default.
• W4306173791 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/36242517" @default.
• W4306173791 hasPublicationYear "2022" @default.
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