Knowledge Bank

Occlusive arterial thrombosis leading to stroke and myocardial infarction contribute to ~13 million global deaths annually. In 1995, Intravenous recombinant tissue plasminogen activator (rTPA) represented a breakthrough in stroke therapy, reducing morbidity and improving functional outcomes. However, it was found that patients treated with rTPA routinely result in inadequate recanalization in the setting of large vessel occlusion, experienced restenosis, and suffered from symptomatic intracranial hemorrhage (ICH). Moreover, given that patients must receive rTPA within 3 to 4.5 hours from symptom onset and not have one of the 18-point exclusion criteria, only ~6% of patients received rTPA of the 690,000 ischemic stroke incidents that occurred in 2017. Given all of this, a change from the current stroke therapeutics must be investigated to improve safety and efficacy. Aptamers are single-stranded oligonucleotides (RNA and DNA) that can bind to and inhibit targeted proteins. Unlike rTPA and parenteral anti-platelet drugs, aptamers can be reversed with antidote oligonucleotides, that bind to the aptamer via Watson-Crick base-pairing without perturbing platelet reactivity. In this study, we propose a paradigm shift from the current stroke therapeutics to a new target resulting in a more effective, safer, and readily reversible anti-thrombotic agent. Our laboratory has developed an RNA aptamer therapeutic (DTRI-031) which directly inhibits von Willebrand Factor (VWF)-mediated platelet adhesion and aggregation. Along with a matched antidote DTRI-025 to control its activity, we demonstrate that DTRI-031 can lyse stabilized clots in a safer and more effective fashion than rTPA. Furthermore, the information included in this project can provide considerable insight into the use of antidote molecules for safer therapeutic drugs.