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Generation of a humanized FXII knock-in mouse-A powerful model system to test novel anti-thrombotic agents
Sarah Beck1,2, David Stegner1,2, Stefan Loroch3
1Institute of Experimental Biomedicine I, University Hospital Würzburg, Würzburg, Germany.
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 hF12KI 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 hF12KI mice in an arterial thrombosis model without affecting bleeding times.
Conclusion:
These data establish the newly generated hF12KI 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.
Insights
Researchers developed a humanized FXII mouse model to study FXIIa inhibitors. This model effectively reduces thrombosis without increasing bleeding risk, aiding the development of safer antithrombotic therapies.
Area of Science:
- Hemostasis and Thrombosis Research
- Pharmacology and Drug Development
- Genetically Engineered Animal Models
Background:
- Thrombosis treatment faces challenges in preventing bleeding complications.
- Inhibiting coagulation factor XII (FXII) shows promise for safe antithrombosis.
- Current animal models hinder in vivo studies of human FXII inhibitors.
Purpose of the Study:
- To develop and characterize a novel humanized FXII mouse model.
- To enable in vivo assessment of human FXII(a) inhibitors.
- To facilitate the development of safe and effective antithrombotic therapies.
Main Methods:
- Generated a humanized FXII mouse model via genetic knock-in of the human F12 gene.
- Conducted in vitro coagulation assays and in vivo thrombosis models.
- Utilized an anti-human FXIIa antibody (3F7) for targeted inhibition studies.
Main Results:
- Humanized FXII mice (hF12KI) exhibited normal coagulation and platelet function.
- Targeting FXIIa with 3F7 increased activated partial thromboplastin time dose-dependently.
- hF12KI mice were protected in an arterial thrombosis model without increased bleeding.
Conclusions:
- The hF12KI mouse is a unique and powerful model for in vivo studies of anti-FXII(a) biologics.
- This model supports the development of FXII(a) inhibitors with improved safety profiles.
- Facilitates advancement of novel antithrombotic strategies targeting FXII.
