ArticleMolecular therapy : the journal of the American Society of Gene Therapy2009
Enhanced factor VIII heavy chain 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 19 papers.
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Who cites it
19 citing papers in PubMed, 30 citations in OpenAlex.
- Genome-wide CRISPR screenings identified SMCHD1 as a host-restricting factor for AAV transduction.PLoS pathogens · 2024Article
- Liver gene therapy with intein-mediated F8 trans-splicing corrects mouse haemophilia A.EMBO molecular medicine · 2022Article
- Minimal Essential Human Factor VIII Alterations Enhance Secretion and Gene Therapy Efficiency.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
- Evaluation of the activity levels of rat FVIII and human FVIII delivered by adeno-associated viral vectors both in vitro and in vivo.Blood cells, molecules & diseases · 2018Article
- Syngeneic AAV Pseudo-particles Potentiate Gene Transduction of AAV Vectors.Molecular therapy. Methods & clinical development · 2017Article
- High-Density Recombinant Adeno-Associated Viral Particles are Competent Vectors for In Vivo Transduction.Human gene therapy · 2016Article
- Evaluation of the biological differences of canine and human factor VIII in gene delivery: implications in human hemophilia treatment.Gene therapy · 2016Article
- Gene therapy for hemophilia.Frontiers in bioscience (Landmark edition) · 2015Review
- Efficient production of dual recombinant adeno-associated viral vectors for factor VIII delivery.Human gene therapy methods · 2014Article
- A concept of eliminating nonhomologous recombination for scalable and safe AAV vector generation for human gene therapy.Nucleic acids research · 2013Article
- Article
- Liver-Directed Adeno-Associated Viral Gene Therapy for Hemophilia.Journal of genetic syndromes & gene therapy · 2012Article
- Engineering Factor Viii for Hemophilia Gene Therapy.Journal of genetic syndromes & gene therapy · 2011Article
- Systemic elimination of de novo capsid protein synthesis from replication-competent AAV contamination in the liver.Human gene therapy · 2011Article
- Proteasome inhibitors enhance gene delivery by AAV virus vectors expressing large genomes in hemophilia mouse and dog models: a strategy for broad clinical application.Molecular therapy : the journal of the American Society of Gene Therapy · 2010Article
- Characterization of genome integrity for oversized recombinant AAV vector.Molecular therapy : the journal of the American Society of Gene Therapy · 2010Article
- Advancements in gene transfer-based therapy for hemophilia A.Expert review of hematology · 2009Article
- Protein replacement therapy and gene transfer in canine models of hemophilia A, hemophilia B, von willebrand disease, and factor VII deficiency.ILAR journal · 2009Review
Corrections and comments
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Authors and funding
8 authors at 4 institutions in 2 countries.
Funding
Abstract
Hemophilia A gene therapy using recombinant adenovirus-associated virus (AAV) vectors has been hampered by the size of the factor VIII (FVIII) cDNA. Previously, splitting the FVIII coding sequence into a heavy-chain (HC) fragment and a light-chain (LC) fragment for dual recombinant AAV vector delivery has been successfully explored. However, the main disadvantage of this approach is a "chain imbalance" problem in which LC secretion is approximately 1-2 logs higher than that of HC, and therefore, the majority of protein synthesized is nonfunctional. To improve HC secretion, we constructed alternate FVIII HCs based on our observation that LC facilitates HC secretion. To our surprise, most of the new HC molecules exhibited enhanced expression over the traditional HC molecule (HC(745)). The optimized HC mutein, HC(HL), including additional acidic-region-3 (ar3) sequences, exhibited three- to fivefold higher activity in both enzyme-linked immunosorbent assay (ELISA) and activated partial thromboplastin time (aPTT) assay in in vitro testing. Further characterization suggested ar3 sequences increased HC secretion, rather than promoting HC synthesis. Intravenous delivery of AAV8-HC(HL)+AAV8-LC or AAV8-HC(745)+AAV8-LC achieved phenotypic correction in hemophilia A mice. Mice receiving AAV8-HC(HL)+AAV8-LC achieved three- to fourfold higher HC expression than AAV8-HC(745)+AAV8-LC, consistent with the FVIII functional assays. HC(HL) should be substituted for HC(745) in a dual AAV vector strategy due to its enhanced expression.
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