Humanized Glycoprotein VI Mouse to Study Anti-Glycoprotein VI Agents In Vivo

The search for better antiplatelet drugs that efficiently prevent platelet thrombus formation while having a minimal effect on general hemostasis remains a competitive challenge. Glycoprotein VI (GPVI) is considered to be an attractive target for the development of new antithrombotic agents. Mangin et al. developed a genetically modified mouse expressing human GPVI (hGPVI) as a preclinical tool to evaluate the role of human GPVI in various models of thrombosis and to screen anti-GPVI compounds. The mice were viable, fertile, and without hematological defects; platelet aggregation, fibrinogen binding, and P-selectin exposures were normal in response to various agonists. The blocking antibody Fab fragment 9O12.2 (anti-GPVI) inhibited collagen-induced platelet aggregation in vitro and ex vivo. In hGPVI mice, 9O12.2 did not prolong tail bleeding time or increase blood loss. The hGPVI model therefore offers the possibility of establishing the bleeding tendency of anti-GPVI compounds alone or associated in dual or tri-therapy with other antiplatelet agents. This unique animal model may permit evaluation of agents targeting human GPVI in terms of efficacy and safety and enable one to determine more relevant human doses and therapeutic combinations, which may help design future clinical studies.

See article at J Pharmacol Exp Ther 2012, 341:156–163.