ArticleMolecular therapy : the journal of the American Society of Gene Therapy2009
Directed engineering of a high-expression chimeric transgene as a strategy for gene therapy of hemophilia A.
Article in Molecular therapy : the journal of the American Society of Gene Therapy, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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Who cites it
50 citing papers in PubMed, 78 citations in OpenAlex.
- Antimetabolites synergize with non-genotoxic antibody drug conjugate conditioning in hematopoietic stem cell lentiviral gene therapy.Molecular therapy. Advances · 2026Article
- Hemophilia A: An Ideal Disease for Prenatal Therapy.Prenatal diagnosis · 2025Review
- 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
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- Roctavian gene therapy for hemophilia A.Blood advances · 2024Review
- Humanization and functional characterization of enhanced coagulation factor IX variants identified through ancestral sequence reconstruction.Journal of thrombosis and haemostasis : JTH · 2024Article
- Altered cleavage of human factor VIII at the B-domain and acidic region 3 interface enhances expression after gene therapy in hemophilia A mice.Journal of thrombosis and haemostasis : JTH · 2023Article
- Pharmacokinetic analysis identifies a factor VIII immunogenicity threshold after AAV gene therapy in hemophilia A mice.Blood advances · 2022Article
- Comparison of different gene addition strategies to modify placental derived-mesenchymal stromal cells to produce FVIII.Frontiers in immunology · 2022Article
- Non-genotoxic conditioning facilitates hematopoietic stem cell gene therapy for hemophilia A using bioengineered factor VIII.Molecular therapy. Methods & clinical development · 2021Article
- Investigating Optimal Autologous Cellular Platforms for Prenatal or Perinatal Factor VIII Delivery to Treat Hemophilia A.Frontiers in cell and developmental biology · 2021Article
- Minimal Essential Human Factor VIII Alterations Enhance Secretion and Gene Therapy Efficiency.Molecular therapy. Methods & clinical development · 2020Article
- Defining the Optimal FVIII Transgene for Placental Cell-Based Gene Therapy to Treat Hemophilia A.Molecular therapy. Methods & clinical development · 2020Article
- B Cell Depletion Eliminates FVIII Memory B Cells and Enhances AAV8-coF8 Immune Tolerance Induction When Combined With Rapamycin.Frontiers in immunology · 2020Article
- The Immune Response to the fVIII Gene Therapy in Preclinical Models.Frontiers in immunology · 2020Review
- The 3.2 Å structure of a bioengineered variant of blood coagulation factor VIII indicates two conformations of the C2 domain.Journal of thrombosis and haemostasis : JTH · 2020Article
- Protein-Engineered Coagulation Factors for Hemophilia Gene Therapy.Molecular therapy. Methods & clinical development · 2019Review
- Preclinical Development of a Hematopoietic Stem and Progenitor Cell Bioengineered Factor VIII Lentiviral Vector Gene Therapy for Hemophilia A.Human gene therapy · 2018Article
- Target-Cell-Directed Bioengineering Approaches for Gene Therapy of Hemophilia A.Molecular therapy. Methods & clinical development · 2018Article
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
Human coagulation factor VIII (fVIII) is inefficiently biosynthesized in vitro and has proven difficult to express at therapeutic levels using available clinical gene-transfer technologies. Recently, we showed that a porcine and certain hybrid human/porcine fVIII transgenes demonstrate up to 100-fold greater expression than human fVIII. In this study, we extend these results to describe the use of a humanized, high-expression, hybrid human/porcine fVIII transgene that is 89% identical to human fVIII and was delivered by lentiviral vectors (LVs) to hematopoietic stem cells for gene therapy of hemophilia A. Recombinant human immunodeficiency virus-based vectors encoding the fVIII chimera efficiently transduced human embryonic kidney (HEK)-293T cells. Cells transduced with hybrid human/porcine fVIII encoding vectors expressed fVIII at levels 6- to 100-fold greater than cells transduced with vectors encoding human fVIII. Transplantation of transduced hematopoietic stem and progenitor cells into hemophilia A mice resulted in long-term fVIII expression at therapeutic levels despite <5% genetically modified blood mononuclear cells. Furthermore, the simian immunodeficiency virus (SIV) -derived vector effectively transduced the human hematopoietic cell lines K562, EU1, U.937, and Jurkat as well as the nonhematopoietic cell lines, HEK-293T and HeLa. All cell lines expressed hybrid human/porcine fVIII, albeit at varying levels with the K562 cells expressing the highest level of the hematopoietic cell lines. From these studies, we conclude that humanized high-expression hybrid fVIII transgenes can be utilized in gene therapy applications for hemophilia A to significantly increase fVIII expression levels compared to what has been previously achieved.
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