title: A reversible aptamer improves outcome and safety in murine models of stroke and hemorrhage.
abstract: Treatment of acute ischemic stroke with intravenous tissue-type plasminogen activator is underutilized partly due to the risk of life-threatening hemorrhage. In response to the clinical need for safer stroke therapy, we explored using an aptamer-based therapeutic strategy to promote cerebral reperfusion in a murine model of ischemic stroke. Aptamers are nucleic acid ligands that bind to their targets with high affinity and specificity, and can be rapidly reversed with an antidote. Here we show that a Factor IXa aptamer administered intravenously after 60 minutes of cerebral ischemia and reperfusion improved neurological function and was associated with reduced thrombin generation and decreased inflammation. Moreover, when the aptamer was administered in the setting of intracranial hemorrhage, treatment with its specific antidote reduced hematoma volume and improved survival. The ability to rapidly reverse a pharmacologic agent that improves neurological function after ischemic stroke should intracranial hemorrhage arise indicates that aptamer-antidote pairs may represent a novel, safer approach to treatment of stroke.
authors.affiliation: Duke University, Durham, North Carolina, USA.
authors.forename: Charlene M
authors.initials: CM
authors.lastname: Blake
authors.forename: Haichen
authors.initials: H
authors.lastname: Wang
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Laskowitz
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Sullenger
mesh_terms: D000818:Animals; D000931:Antidotes / Q000008:administration & dosage / Q000138:chemical synthesis / Q000627:therapeutic use*; D052157:Aptamers, Nucleotide / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000627:therapeutic use*; D002545:Brain Ischemia / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D002543:Cerebral Hemorrhage / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D004195:Disease Models, Animal; D015949:Factor IXa / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use*; D006406:Hematoma; D007249:Inflammation; D007262:Infusions, Intravenous; D051379:Mice; D015424:Reperfusion; D020521:Stroke / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology; D015996:Survival Rate; D013917:Thrombin / Q000032:analysis; D016896:Treatment Outcome
chemical_list: D000931:Antidotes; D052157:Aptamers, Nucleotide; D015949:Factor IXa; D013917:Thrombin