ArticleJournal of thrombosis and haemostasis : JTH2010
Clinical and molecular characterization of a re-established line of sheep exhibiting hemophilia A.
Article in Journal of thrombosis and haemostasis : JTH, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers, 1 of them a synthesis that pooled it.
What it found
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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.
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Who cites it
37 citing papers in PubMed, 1 synthesis or guideline pooled it, 66 citations in OpenAlex.
- Allometry of factor VIII and informed scaling of next-generation therapeutic proteins.Journal of pharmaceutical sciences · 2013Pooled it
- Translational insights from nonclinical studies of AAV gene therapies for hemophilia: mechanisms underpinning variability and durability of gene expression.Therapeutic advances in hematology · 2026Review
- Hemophilia A: An Ideal Disease for Prenatal Therapy.Prenatal diagnosis · 2025Review
- Transplanted gene-modified placental cells boost FVIII activity in pediatric sheep without eliciting immunity, toxicity, or adverse events.Frontiers in immunology · 2025Article
- Generation of Mouse Model of Hemophilia A by Introducing Novel Mutations, Using CRISPR/Nickase Gene Targeting System.Cell journal · 2023Article
- Transplanting FVIII/ET3-secreting cells in fetal sheep increases FVIII levels long-term without inducing immunity or toxicity.Nature communications · 2023Article
- Gene modification therapies for hereditary diseases in the fetus.Prenatal diagnosis · 2023Review
- Ultrasound-mediated gene delivery of factor VIII plasmids for hemophilia A gene therapy in mice.Molecular therapy. Nucleic acids · 2022Article
- Gene and Stem Cell Therapies for Fetal Care: A Review.JAMA pediatrics · 2020Review
- FVIII activity following FVIII protein infusion or FVIII gene transfer predicts the bleeding risk in hemophilia A rats.Journal of thrombosis and haemostasis : JTH · 2020Article
- Defining the Optimal FVIII Transgene for Placental Cell-Based Gene Therapy to Treat Hemophilia A.Molecular therapy. Methods & clinical development · 2020Article
- Therapeutic Mesenchymal Stromal Cells for Immunotherapy and for Gene and Drug Delivery.Molecular therapy. Methods & clinical development · 2020Review
- Protein-Engineered Coagulation Factors for Hemophilia Gene Therapy.Molecular therapy. Methods & clinical development · 2019Review
- Gene-based FVIIa prophylaxis modulates the spontaneous bleeding phenotype of hemophilia A rats.Blood advances · 2019Article
- Characterization of a genetically engineered mouse model of hemophilia A with complete deletion of the F8 gene.Journal of thrombosis and haemostasis : JTH · 2016Article
- Severe Hemophilia A in a Male Old English Sheep Dog with a C→T Transition that Created a Premature Stop Codon in Factor VIII.Comparative medicine · 2016Article
- Current animal models of hemophilia: the state of the art.Thrombosis journal · 2016Review
- In utero stem cell transplantation and gene therapy: rationale, history, and recent advances toward clinical application.Molecular therapy. Methods & clinical development · 2016Review
- Successful Phenotype Improvement following Gene Therapy for Severe Hemophilia A in Privately Owned Dogs.PloS one · 2016Article
- Large animal models of rare genetic disorders: sheep as phenotypically relevant models of human genetic disease.Orphanet journal of rare diseases · 2015Review
Corrections and comments
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Authors and funding
22 authors at 6 institutions in 2 countries.
Funding
Abstract
backgroundLarge animal models that accurately mimic human hemophilia A (HA) are in great demand for developing and testing novel therapies to treat HA.
objectivesTo re-establish a line of sheep exhibiting a spontaneous bleeding disorder closely mimicking severe human HA, fully characterize their clinical presentation, and define the molecular basis for disease. PATIENTS/
methodsSequential reproductive manipulations were performed with cryopreserved semen from a deceased affected ram. The resultant animals were examined for hematologic parameters, clinical symptoms, and responsiveness to human FVIII (hFVIII). The full coding region of sheep FVIII mRNA was sequenced to identify the genetic lesion. RESULTS AND
conclusionsThe combined reproductive technologies yielded 36 carriers and 8 affected animals. The latter had almost non-existent levels of FVIII:C and extremely prolonged aPTT, with otherwise normal hematologic parameters. These animals exhibited bleeding from the umbilical cord, prolonged tail and nail cuticle bleeding time, and multiple episodes of severe spontaneous bleeding, including hemarthroses, muscle hematomas and hematuria, all of which responded to hFVIII. Inhibitors of hFVIII were detected in four treated animals, further establishing the preclinical value of this model. Sequencing identified a premature stop codon and frame-shift in exon 14, providing a molecular explanation for HA. Given the decades of experience using sheep to study both normal physiology and a wide array of diseases and the high homology between human and sheep FVIII, this new model will enable a better understanding of HA and facilitate the development and testing of novel treatments that can directly translate to HA patients.
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Registered trials
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