R44NS122604

Acute ischemic stroke (AIS) results from a blood clot in the neurovasculature and is the 5th leading cause of death and 1st leading cause of 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 of care AIS therapies include the use of the FDA approved thrombolytic agent alteplase (i.e., tissue plasminogen activator) 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 ~15% improvement in stroke outcomes with ~10% fully recovering. However, due to the ~7% dose-dependent associated hemorrhage rate of alteplase, thrombolysis is contraindicated for mild and wake-up strokes which together make up ~60% of all AIS events. Due to safety concerns and limited reliability, usage of thrombolysis in the US remains low (~10%) with 90% of all AIS victims receiving only palliative care. There remains an urgent need to improve first line use of thrombolysis which can be expanded to all AIS victims. UNandUP has invented a novel thrombolysis platform to safely accelerate alteplase to the obstructing blood clot, thereby overcoming the restrictive hemodynamics known to prevent alteplase from quickly reaching the occlusion. The proposed magnetic infusion platform overcomes this barrier by 1) adjunctively conveying alteplase to the clot’s surface more than 100X faster than normal biological diffusion (i.e., minutes vs. hours), and 2) mechanically mixing alteplase at the clot’s surface so that lysis is more reliable. Because alteplase is not conjugated and the mode of action is purely mechanical in nature, FDA meetings confirmed a CDRH IDE pathway is appropriate in support of an FDA Early Feasibility Study, which is a shorter and less expensive pathway compared to a CDER IND process. Importantly, the technology is affordable, does not require precise focusing, and can be configured to travel with patients transferred between hospitals for thrombectomy. Once proven safe and effective using current FDA approved alteplase labeling, UNandUP intends to expand thrombolysis to mild and wake up strokes by increasing the lysis efficacy of smaller alteplase doses known not to induce hemorrhage. If successful, thrombolysis could be safely extended to all 700,000 AIS victims for the first time, which is 10X more than currently treated. The project’s aims include 1) building the magnetic infusion subcomponents (magnetic workstation, silica coated iron nanoparticles, nanoparticle delivery system), and conducting 2) mechanism of action, 3) in vivo safety, and 4) clot interaction studies. Data obtained for the proposed effort will be critical to address FDA concerns in advance of an FDA Early Feasibility Study IDE.There are more than 700,000 annual acute ischemic stroke (AIS) events in the US which result in more than 150,000 deaths, making AIS the fifth leading cause of death and the leading cause of neurological disability. Although thrombectomy is the standard of care for those diagnosed with a treatable large vessel occlusion in the anterior circulation, a majority of AIS events are not amenable to thrombectomy; thus, improvements in thrombolysis are needed in that 1) thrombolysis currently results in only a ~10% chance of full recovery; 2) due to dose-related hemorrhage risks of thrombolysis, mild and wake-up strokes remain contraindicated for thrombolysis despite making up nearly 60% of all strokes; and 3) AIS patients who are thrombolyzed during transfer often arrive too late to benefit from thrombectomy. UNandUP (short for “Unmet Needs and Underserved Populations”) has invented a novel thrombolysis platform which promises to be more effective (by adjunctively lysing occlusive clots faster and more reliably) and safer (by subsequently lowering the systemic thrombolytic dose associated with hemorrhage), so that all AIS victims can be better treated.