ArticleJournal of thrombosis and haemostasis : JTH2011
Functional factor VIII made with von Willebrand factor at high levels in transgenic milk.
Article in Journal of thrombosis and haemostasis : JTH, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 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.
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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.
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Who cites it
5 citing papers in PubMed, 15 citations in OpenAlex.
- Article
- Investigation of hFVIII production in mammary glands of transgenic mice.Monoclonal antibodies in immunodiagnosis and immunotherapy · 2014Article
- Blood Clotting Factor VIII: From Evolution to Therapy.Acta naturae · 2013Article
- New treatments in hemophilia: insights for the clinician.Therapeutic advances in hematology · 2012Article
- Engineering Factor Viii for Hemophilia Gene Therapy.Journal of genetic syndromes & gene therapy · 2011Article
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
Abstract
backgroundCurrent manufacturing methods for recombinant human factor VIII (rFVIII) within mammalian cell cultures are inefficient, hampering the production of sufficient amounts for affordable, worldwide treatment of hemophilia A. However, rFVIII has been expressed at very high levels by the transgenic mammary glands of mice, rabbits, sheep, and pigs. Unfortunately, it is secreted into milk with low specific activity, owing in part to the labile, heterodimeric structure that results from furin processing of its B domain.
objectivesTo express biologically active rFVIII in the milk of transgenic mice through targeted bioengineering.
methodsTransgenic mice were made with a mammary-specific FVIII gene (226/N6) bioengineered for efficient expression and stability, encoding a protein containing a B domain with no furin cleavage sites. 226/N6 was expressed with and without von Willebrand factor (VWF). 226/N6 was evaluated by ELISA, SDS-PAGE, western blot, and one-stage and two-stage clotting assays. The hemostatic activity of immunoaffinity-enriched 226/N6 was studied in vivo by infusion into hemophilia A knockout mice. RESULTS AND
conclusionsWith or without coexpression of VWF, 226/N6 was secreted into milk as a biologically active single-chain molecule that retained high specific activity, similar to therapeutic-grade FVIII. 226/N6 had > 450-fold higher IU mL(-1) than previously reported in cell culture for rFVIII. 226/N6 exhibited similar binding to plasma-derived VWF as therapeutic-grade rFVIII, and intravenous infusion of transgenic 226/N6 corrected the bleeding phenotype of hemophilia A mice. This provides proof-of-principle for the study of expression of 226/N6 and perhaps other single-chain bioengineered rFVIIIs in the milk of transgenic livestock.
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Registered trials
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