ArticleMolecular therapy : the journal of the American Society of Gene Therapy2022
Ectopic clotting factor VIII expression and misfolding in hepatocytes as a cause for hepatocellular carcinoma.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers, 1 of them a synthesis that pooled it.
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Who cites it
24 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Liver-related aspects of valoctocogene roxaparvovec gene therapy for hemophilia A: expert guidance for clinical practice.Blood advances · 2024Guideline
- An ER stress-responsive RNA rheostat for programmable gene and mRNA therapies.Cell chemical biology · 2026Article
- Integrated serum proteomics and metabolomics reveal an INR-associated multi-omics signature in hepatocellular carcinoma.Clinical proteomics · 2026Article
- Transforming Hemophilia Management: Lessons from Gene Therapy Clinical Trials.Molecular biotechnology · 2026Review
- Ribosomal read through as an alternative therapy for patients with hemophilia with nonsense mutations.Journal of thrombosis and haemostasis : JTH · 2026Article
- Malignancy and gene therapy in hemophilia.Research and practice in thrombosis and haemostasis · 2026Article
- Exploring gene editing as a potential therapeutic strategy for hemophilia.Frontiers in bioengineering and biotechnology · 2026Review
- Translational insights from nonclinical studies of AAV gene therapies for hemophilia: mechanisms underpinning variability and durability of gene expression.Therapeutic advances in hematology · 2026Review
- The Roles and Clinical Significance of Major Hepatic-Derived Metabolites in Hepatocellular Carcinoma.Journal of gastroenterology and hepatology · 2025Review
- Gene therapy as an innovative approach to the treatment of hemophilia B-a review.Journal of applied genetics · 2025Review
- Enhancing the potency of in vivo lentiviral vector mediated gene therapy to hepatocytes.Nature communications · 2025Article
- Gene therapy for hemophilia - From basic science to first approvals of "one-and-done" therapies.Molecular therapy : the journal of the American Society of Gene Therapy · 2025Review
- Preclinical development of TAK-754, a high-performance AAV8-based vector expressing coagulation factor VIII.Molecular therapy. Methods & clinical development · 2025Article
- Review
- Optimizing liver health before and after gene therapy for hemophilia A.Blood advances · 2024Review
- Exosomal misfolded proteins released by cancer stem cells: dual functions in balancing protein homeostasis and orchestrating tumor progression.Discover oncology · 2024Review
- Gene editing therapy for cardiovascular diseases.MedComm · 2024Review
- GP64-pseudotyped lentiviral vectors target liver endothelial cells and correct hemophilia A mice.EMBO molecular medicine · 2024Article
- Ultrasound-mediated gene delivery specifically targets liver sinusoidal endothelial cells for sustained FVIII expression in hemophilia A mice.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
- Analysis of vector genome integrations in multicentric lymphoma after AAV gene therapy in a severe hemophilia A dog.Molecular therapy. Methods & clinical development · 2023Article
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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.
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