Project Grant R44NS132605

LOW-DOSE MAGNETO-THROMBOLYSIS TO EXPAND STROKE CARE - ACUTE ISCHEMIC STROKE (AIS) RESULTS FROM A BLOOD CLOT IN THE NEUROVASCULATURE AND IS A LEADING CAUSE OF DEATH AND NEUROLOGICAL DISABILITY IN THE UNITED STATES (US). AIS IMPACTS MORE THAN 700,000 AMERICANS ANNUALLY, WITH A 65% CHANCE OF DEATH OR SEVERE DISABILITY. BY 2030, IT IS EXPECTED THAT THE AIS ECONOMIC BURDEN WILL EXCEED $180B IN THE US ALONE. STANDARD AIS THERAPIES INCLUDE FDA-APPROVED THROMBOLYSIS USING ALTEPLASE (I.E., TISSUE PLASMINOGEN ACTIVATOR, TPA) WITHIN 4.5 HOURS OF STROKE ONSET AND EARLIEST-POSSIBLE THROMBECTOMY FOR LARGE VESSEL OCCLUSIONS (OUT TO 24HRS). IN CONTRAST TO THROMBECTOMY, THROMBOLYSIS DOES NOT REQUIRE CONFIRMATION OF A VESSEL OCCLUSION. BECAUSE ONLY ~10% OF AIS VICTIMS ARE ELIGIBLE FOR THROMBECTOMY, THROMBOLYSIS REMAINS A CRITICAL FIRST LINE TOOL TO TREAT THOSE DIAGNOSED WITH AIS. WHEN EMPLOYED, THROMBOLYSIS IS ASSOCIATED WITH A MODEST ~15% IMPROVEMENT IN STROKE OUTCOMES, RESULTING IN ONLY ~10% FULLY RECOVERING. HOWEVER, DUE TO ALTEPLASE'S ~7% DOSE-DEPENDENT HEMORRHAGE RISK, THROMBOLYSIS REMAINS CONTRAINDICATED FOR MILD AND WAKE-UP STROKES WHICH TOGETHER MAKE UP ~60% OF ALL AIS EVENTS. CURRENTLY, THROMBOLYSIS USAGE WITHIN THE US REMAINS LOW (~10%) WITH 90% OF ALL AIS VICTIMS ONLY RECEIVING PALLIATIVE CARE. THUS, THERE IS AN URGENT NEED TO IMPROVE THE EFFICACY AND SAFETY OF THROMBOLYSIS AND EXTEND THROMBOLYSIS TO MORE AIS VICTIMS. UNANDUP HAS INVENTED A NOVEL NANOPARTICLE-BASED THROMBOLYSIS PLATFORM TO SAFELY ACCELERATE ALTEPLASE TO AIS-ASSOCIATED BLOOD CLOTS, THEREBY OVERCOMING RESTRICTIVE HEMODYNAMICS KNOWN TO PREVENT ALTEPLASE FROM REACHING THE OCCLUSION. THE PLATFORM OVERCOMES THIS BARRIER BY 1) CONVEYING ALTEPLASE-CONJUGATED MAGNETIC NANOPARTICLES TO THE CLOT'S SURFACE MORE THAN 350X FASTER THAN NORMAL BIOLOGICAL DIFFUSION (SO THAT LYSIS STARTS WITHIN MINUTES VERSUS HOURS), AND 2) MECHANICALLY MIXING ALTEPLASE AT THE CLOT'S SURFACE TO IMPROVE LYSIS USING AN ALTEPLASE DOSE NEARLY 250X LOWER THAN CURRENTLY APPROVED (WHICH PROMISES TO ELIMINATE ALTEPLASE'S ELEVATED HEMORRHAGE RISK). C3I PARTICIPATION AND FDA/REGULATORY MEETINGS CONFIRM A LIKELY CDER PATHWAY WHICH, ALTHOUGH LENGTHIER AND MORE COSTLY THAN A CDRH PATHWAY, RESULTS IN A COMMERCIALLY ATTRACTIVE PHARMACEUTICAL PRODUCT. THE PLATFORM IS AFFORDABLE TO HOSPITALS, DOES NOT REQUIRE PRECISE KNOWLEDGE OF THE CLOT'S LOCATION, AND IS INTENDED TO SUPPORT EMT TRANSFERS BETWEEN SPOKE AND HUB STROKE CENTERS, THEREBY ENSURING THROMBECTOMY IS NOT DELAYED. ONCE PROVEN SAFE AND EFFECTIVE, UNANDUP'S GOAL IS TO EXTEND THE BENEFITS OF THROMBOLYSIS TO NEARLY ALL 700,000 AIS VICTIMS, WHICH IS 10X MORE THAN CURRENTLY TREATED. BY LEVERAGING UNANDUP'S PRIOR SUCCESS IN DEVELOPING MAGNETIC NANOPARTICLES AND PORTABLE MAGNET SYSTEMS, THE AIMS OF THIS EFFORT CAN FOCUS ON SYNTHESIZING CGMP NANOPARTICLES USING PROPRIETARY MAGNETIC CORES AND CONDUCTING SAFETY AND EFFICACY STUDIES IN SUPPORT OF AN FDA-CDER REGULATORY APPROVAL PROCESS.