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Published on: September 30, 2021
A novel F8 -/- rat as a translational model of human hemophilia A
L N Nielsen1, B Wiinberg, M Häger
1Novo Nordisk, Maaloev, Denmark.
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.
