Identification of new approaches for the treatment of stroke

2019 Vanguard Grant

Years funded: 2020-2021

Acute Ischaemic Stroke (stroke) is the third most-common cause of death and a leading cause of disability. Up to 85% of strokes are caused by blood clots that reduce blood flow to the brain, with the mainstay of stroke treatment being rapid clot removal and restoration of blood flow to the brain. Drugs that degrade the blood clot (recombinant tissue plasminogen activator: rtPA) are currently used to reopen blood vessels, referred to as “Thrombolytic therapy”. However, rtPA has significant limitations which undermine its clinical effectiveness. These include a low success rate in lysing clots in larger arteries, a tendency to promote clot reformation and vessel reocclusion, limited capacity to prevent obstruction in the cerebral microcirculation, and increased risk of life-threatening bleeding in the brain (intracerebral haemorrhage-ICH).

With strict eligibility criteria, rtPA is only administered in 13% of all stroke patients, and less than half of these achieve a good therapeutic outcome. Identification of anticoagulants that can improve the clot-busting potential of rtPA, without causing excess bleeding, would represent a major advance in the treatment of stroke. Unfortunately, all existing anticoagulants used in the clinic cause excessive bleeding, especially when combined with rtPA, thereby prohibiting their use for stroke treatment. We have identified a novel anticoagulant (direct thrombin inhibitor termed MDL-2) which has a unique anticoagulant effect, which unexpectantly, causes minimal bleeding.

In this proposal, we plan to utilise a novel preclinical mouse model of stroke, to investigate the safety and effectiveness of MDL-2 when used in combination with rtPA. Outcomes: The studies outlined in this proposal will help define whether MDL-2 is a safe anticoagulant (has a wide therapeutic window) relative to other anticoagulants used in the clinic. We will also investigate whether MDL-2 can be safely used with rtPA and increase clot lysis in preclinical models, leading to improved stroke outcomes.