TY  - JOUR
A1  - Beck, Sarah
A1  - Stegner, David
A1  - Loroch, Stefan
A1  - Baig, Ayesha A.
A1  - Göb, Vanessa
A1  - Schumbutzki, Cornelia
A1  - Eilers, Eva
A1  - Sickmann, Albert
A1  - May, Frauke
A1  - Nolte, Marc W.
A1  - Panousis, Con
A1  - Nieswandt, Bernhard
T1  - Generation of a humanized FXII knock-in mouse-A powerful model system to test novel anti-thrombotic agents
T2  - Journal of Thrombosis and Haemostasis
N2  - Background
Effective inhibition of thrombosis without generating bleeding risks is a major challenge in medicine. Accumulating evidence suggests that this can be achieved by inhibition of coagulation factor XII (FXII), as either its knock-out or inhibition in animal models efficiently reduced thrombosis without affecting normal hemostasis. Based on these findings, highly specific inhibitors for human FXII(a) are under development. However, currently, in vivo studies on their efficacy and safety are impeded by the lack of an optimized animal model expressing the specific target, that is, human FXII.

Objective
The primary objective of this study is to develop and functionally characterize a humanized FXII mouse model.

Methods
A humanized FXII mouse model was generated by replacing the murine with the human F12 gene (genetic knock-in) and tested it in in vitro coagulation assays and in in vivo thrombosis models.

Results
These hF12\(^{KI}\) mice were indistinguishable from wild-type mice in all tested assays of coagulation and platelet function in vitro and in vivo, except for reduced expression levels of hFXII compared to human plasma. Targeting FXII by the anti-human FXIIa antibody 3F7 increased activated partial thromboplastin time dose-dependently and protected hF12\(^{KI}\) mice in an arterial thrombosis model without affecting bleeding times.

Conclusion
These data establish the newly generated hF12\(^{KI}\) mouse as a powerful and unique model system for in vivo studies on anti-FXII(a) biologics, supporting the development of efficient and safe human FXII(a) inhibitors.
KW  - hemostasis,
KW  - blood coagulation
KW  - factor XII
KW  - animal models
KW  - thrombosis
Y1  - 2021
UR  - https://opus.bibliothek.uni-wuerzburg.de/frontdoor/index/index/docId/25956
UR  - https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-259567
VL  - 19
IS  - 11
ER  -