title: A novel F8 -/- rat as a translational model of human hemophilia A.
abstract: BACKGROUND
  In preclinical hemophilia research, an animal model that reflects both the phenotype and the pathology of the disease is needed.
  
  
  OBJECTIVE
  Here, we describe the generation and characterization of a novel genetically engineered F8(-/-) rat model.
  
  
  METHODS
  The rats were produced on a Sprague Dawley background with the zinc finger nuclease technique. A founder with a 13-bp deletion in exon 16 causing a premature translational stop in the C-terminal part of the A3 domain of factor VIII was selected, and a breeding colony was established.
  
  
  RESULTS
  Seventy per cent of the homozygous rats had clinically manifest spontaneous hemorrhagic episodes that needed treatment. The F8(-/-) rats had no detectable FVIII activity, and had a significantly prolonged activated partial thromboplastin time (APTT) and clot formation time as compared with wild-type (WT)/WT rats. In vitro spiking of rat plasma with human recombinant FVIII resulted in dose-dependent normalization of the APTT.
  
  
  CONCLUSIONS
  On the basis of the targeted deletion in F8, and the distinct physical and analytic characteristics of the rat, we conclude that an FVIII-deficient rat strain has been generated that has the potential to contribute greatly to translational research.
authors.affiliation: Novo Nordisk, Maaloev, Denmark.
authors.forename: L N
authors.initials: LN
authors.lastname: Nielsen
authors.forename: B
authors.initials: B
authors.lastname: Wiinberg
authors.forename: M
authors.initials: M
authors.lastname: Häger
authors.forename: H L
authors.initials: HL
authors.lastname: Holmberg
authors.forename: J J
authors.initials: JJ
authors.lastname: Hansen
authors.forename: K
authors.initials: K
authors.lastname: Roepstorff
authors.forename: M
authors.initials: M
authors.lastname: Tranholm
mesh_terms: D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D004195:Disease Models, Animal; D005169:Factor VIII / Q000235:genetics*; D006467:Hemophilia A / Q000097:blood / Q000235:genetics*; D016133:Polymerase Chain Reaction; D014176:Protein Biosynthesis; D051381:Rats; D055647:Rats, Transgenic
chemical_list: D017931:DNA Primers; D005169:Factor VIII
keywords: Rattus; animal model; gene knockout; hemophilia; phenotype