Reference: PD 13059 

The Problem

Although tissue plasminogen activator (TPA) is an effective therapy for ischemic stroke, it also causes severe and fatal bleeding in some patients.  Fear of bleeding and the lack of a specific antidote has led to widespread underuse of TPA by physicians. Serious bleeding occurs in 7-9% of ischemic stroke patients treated with TPA.  In some cases, high levels of TPA are present in the blood of patients after undergoing bypass surgery; thus leading to serious bleeding.  Many of the currently used antidotes not only inhibit the plasminogen activation system, but also interfere with other molecular pathways. Therefore, there is a need for a therapeutic which specifically targets and inhibits fibrin-dependent plasminogen activation in order to control hemorrhage induced by TPA therapy in ischemic stroke.

The Technology Solution 

Researchers at the University of Tennessee have developed selective inhibitors which inhibit fibrin-dependent plasminogen activation of TPA.  The inhibitors are 2 monoclonal antibodies (TPAi-14 and TPAi-23) which bind with specificity and high affinity to different sites within TPA.  These antibodies can act alone or synergistically to inhibit TPA-induced fibrinolysis of human clots.  When given after the initiation of TPA therapy, TPAi-14 and TPAi-23 reduced brain hemorrhage 5-fold, and surgical bleeding 4-fold, as well as brain cell death in a murine thromboembolic model that simulates human stroke.  These data suggest that fibrin-dependent activation of plasminogen by TPA contributes to hemorrhage and adverse outcomes in stroke, and that targeted inhibitors of this process may prove useful for treating TPA-induced hemorrhage.  To our knowledge, this is the first study demonstrating that specific inhibition of fibrin-dependent activation of TPA reduces brain hemorrhage, infarction and surgical bleeding in thromboembolic ischemic stroke after administration of TPA therapy.

Features and Benefits

•    Effective treatment for TPA-induced hemorrhage

•    Therapeutic inhibitor exhibiting high specificity

•    Potential first therapeutic that reduces hemorrhage after TPA therapy in ischemic stroke.

Patents

Provisional patent application number 61/755,298 filed January 2013.

The Inventor

Dr. Guy Reed is the Chairman of the Department of Medicine at The University of Tennessee Health Science Center.  In his research, he seeks to discover pathogenetic mechanisms of atherothrombosis and heart failure, with the aim of translating those insights into novel therapeutic approaches for patients.