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Platelet-targeted thrombolysis for treatment of acute ischemic stroke

Thrombolysis with tissue-type plasminogen activator (tPA) remains the main treatment for acute ischemic stroke. Nevertheless, tPA intervention is limited by a short therapeutic window, low recanalization rates, and a risk of intracranial hemorrhage (ICH), highlighting the clinical demand for improve...

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Detalles Bibliográficos
Autores principales: Palazzolo, Jason S., Ale, Anukreity, Ho, Heidi, Jagdale, Shweta, Broughton, Brad R. S., Medcalf, Robert L., Wright, David K., Alt, Karen, Hagemeyer, Christoph E., Niego, Be’eri
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The American Society of Hematology 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9984306/
https://www.ncbi.nlm.nih.gov/pubmed/35482909
http://dx.doi.org/10.1182/bloodadvances.2021006691
Descripción
Sumario:Thrombolysis with tissue-type plasminogen activator (tPA) remains the main treatment for acute ischemic stroke. Nevertheless, tPA intervention is limited by a short therapeutic window, low recanalization rates, and a risk of intracranial hemorrhage (ICH), highlighting the clinical demand for improved thrombolytic drugs. We examined a novel thrombolytic agent termed “SCE5-scuPA,” comprising a single-chain urokinase plasminogen activator (scuPA) fused with a single-chain antibody (SCE5) that targets the activated glycoprotein IIb/IIIa platelet receptor, for its effects in experimental stroke. SCE5-scuPA was first tested in a whole blood clot degradation assay to show the benefit of platelet-targeted thrombolysis. The tail bleeding time, blood clearance, and biodistribution were then determined to inform the use of SCE5-scuPA in mouse models of photothrombotic stroke and middle cerebral artery occlusion against tenecteplase. The impacts of SCE5-scuPA on motor function, ICH, blood–brain barrier (BBB) integrity, and immunosuppression were evaluated. Infarct size was measured by computed tomography imaging and magnetic resonance imaging. SCE5-scuPA enhanced clot degradation ex vivo compared with its nonplatelet-targeting control. The maximal SCE5-scuPA dose that maintained hemostasis and a rapid blood clearance was determined. SCE5-scuPA administration both before and 2 hours after photothrombotic stroke reduced the infarct volume. SCE5-scuPA also improved neurologic deficit, decreased intracerebral blood deposits, preserved the BBB, and alleviated immunosuppression poststroke. In middle cerebral artery occlusion, SCE5-scuPA did not worsen stroke outcomes or cause ICH, and it protected the BBB. Our findings support the ongoing development of platelet-targeted thrombolysis with SCE5-scuPA as a novel emergency treatment for acute ischemic stroke with a promising safety profile.