ArticleJCI insight2016
Circumventing furin enhances factor VIII biological activity and ameliorates bleeding phenotypes in hemophilia models.
Article in JCI insight, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
25 citing papers in PubMed, 36 citations in OpenAlex.
- Article
- Loss of factor VIII in zebrafish rebalances antithrombin deficiency but has a limited bleeding diathesis.Blood advances · 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
- Ancient origin of the furin sequence in the wolf F8 gene.Open veterinary journal · 2025Article
- Enhancing hemophilia A gene therapy by strategic F8 deletions in AAV vectors.Blood science (Baltimore, Md.) · 2025Article
- Review
- AAV gene therapy in companion dogs with severe hemophilia: Real-world long-term data on immunogenicity, efficacy, and quality of life.Molecular therapy. Methods & clinical development · 2024Article
- Functional Roles of Furin in Cardio-Cerebrovascular Diseases.ACS pharmacology & translational science · 2024Review
- Loss of factor VIII in zebrafish rebalances antithrombin deficiency but has a limited bleeding diathesis.bioRxiv : the preprint server for biology · 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
- Cellular stress and coagulation factor production: when more is not necessarily better.Journal of thrombosis and haemostasis : JTH · 2023Review
- Functional analysis of rare genetic variants in complement factor I in advanced age-related macular degeneration.Human molecular genetics · 2022Article
- Article
- Platelet-inspired therapeutics: current status, limitations, clinical implications, and future potential.Drug delivery and translational research · 2021Review
- Enhancing therapeutic efficacy of in vivo platelet-targeted gene therapy in hemophilia A mice.Blood advances · 2020Article
- A Molecular Revolution in the Treatment of Hemophilia.Molecular therapy : the journal of the American Society of Gene Therapy · 2020Review
- Correction of bleeding in experimental severe hemophilia A by systemic delivery of factor VIII-encoding mRNA.Haematologica · 2020Article
- Translational Potential of Immune Tolerance Induction by AAV Liver-Directed Factor VIII Gene Therapy for Hemophilia A.Frontiers in immunology · 2020Review
- Protein-Engineered Coagulation Factors for Hemophilia Gene Therapy.Molecular therapy. Methods & clinical development · 2019Review
- Update on clinical gene therapy for hemophilia.Blood · 2019Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
11 authors at 3 institutions in 1 country.
Funding
Abstract
Processing by the proprotein convertase furin is believed to be critical for the biological activity of multiple proteins involved in hemostasis, including coagulation factor VIII (FVIII). This belief prompted the retention of the furin recognition motif (amino acids 1645-1648) in the design of B-domain-deleted FVIII (FVIII-BDD) products in current clinical use and in the drug development pipeline, as well as in experimental FVIII gene therapy strategies. Here, we report that processing by furin is in fact deleterious to FVIII-BDD secretion and procoagulant activity. Inhibition of furin increases the secretion and decreases the intracellular retention of FVIII-BDD protein in mammalian cells. Our new variant (FVIII-ΔF), in which this recognition motif is removed, efficiently circumvents furin. FVIII-ΔF demonstrates increased recombinant protein yields, enhanced clotting activity, and higher circulating FVIII levels after adeno-associated viral vector-based liver gene therapy in a murine model of severe hemophilia A (HA) compared with FVIII-BDD. Moreover, we observed an amelioration of the bleeding phenotype in severe HA dogs with sustained therapeutic FVIII levels after FVIII-ΔF gene therapy at a lower vector dose than previously employed in this model. The immunogenicity of FVIII-ΔF did not differ from that of FVIII-BDD as a protein or a gene therapeutic. Thus, contrary to previous suppositions, FVIII variants that can avoid furin processing are likely to have enhanced translational potential for HA therapy.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.