A novel F8 -/- rat as a translational model of human hemophilia A
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A novel F8 -/- rat as a translational model of human hemophilia A. / Nielsen, L. N.; Wiinberg, B.; Häger, M.; Holmberg, H. L.; Hansen, J. J.; Roepstorff, K.; Tranholm, M.
I: Journal of Thrombosis and Haemostasis, Bind 12, Nr. 8, 08.2014, s. 1274-1282.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - A novel F8 -/- rat as a translational model of human hemophilia A
AU - Nielsen, L. N.
AU - Wiinberg, B.
AU - Häger, M.
AU - Holmberg, H. L.
AU - Hansen, J. J.
AU - Roepstorff, K.
AU - Tranholm, M.
PY - 2014/8
Y1 - 2014/8
N2 - Background: In preclinical hemophilia research, an animal model that reflects both the phenotype and the pathology of the disease is needed. Objectives: 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. Conclusion: 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.
AB - Background: In preclinical hemophilia research, an animal model that reflects both the phenotype and the pathology of the disease is needed. Objectives: 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. Conclusion: 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.
KW - Animal model
KW - Gene knockout
KW - Hemophilia
KW - Phenotype
KW - Rattus
UR - http://www.scopus.com/inward/record.url?scp=84905657066&partnerID=8YFLogxK
U2 - 10.1111/jth.12635
DO - 10.1111/jth.12635
M3 - Journal article
C2 - 24931420
AN - SCOPUS:84905657066
VL - 12
SP - 1274
EP - 1282
JO - Journal of Thrombosis and Haemostasis
JF - Journal of Thrombosis and Haemostasis
SN - 1538-7933
IS - 8
ER -
ID: 345682769