COUNTERSTROKE · Treating stroke with Affibody molecules targeting the inflammatory mediator HMGB1

The scope of the project is to generate a candidate drug targeting the inflammatory mediator High mobility group box 1 protein (HMGB1) to be used in treatment of stroke. The candidate drug will be validated in animal models, characterized and optimized for subsequent clinical development.Stroke remains a leading cause of death and disability throughout the world. Within EU, more than 500 000 persons die of stroke each year. Of those surviving stroke, 50% are left with physical or cognitive impairment and the total annual cost of stroke is estimated at Euro 27 billion.Stroke occurs as a consequence of hemorrhagic insult or artery occlusion due to underlying cardiovascular disease. Pivotal in beneficial treatment of stroke is instant intervention. Blood clot dissolution using recombinant tissue plasminogen activator is the only pharmacological treatment demonstrated to limit neurological damage in stroke, but is only effective for patients who present within 3 hours after stroke onset. Thus there is an unmet need for an efficacious therapy that can be administered within and beyond 3 hours to achieve neuroprotection. HMGB1, released during the cerebral ischemic event and the subsequent neuroinflammation, is a well-characterized mediator of inflammation. Beneficial effects of blocking HMGB1 is proven in preclinical stroke studies. The drug to be developed is an Affibody molecule binding to and neutralizing HMGB1. Affibody molecules are engineered proteins significantly smaller than antibodies and therefore having favorable biodistribution properties, and a history of being efficient and non-toxic in clinical trials. In this application, we describe a multidisciplinary research consortium with Europe´s leading scientists in HMGB1 research and in registry-based clinical trial and dissemination methodology. The consortium has unique potentials to bring a new treatment principle against cerebral stroke to clinical reality.