Abstract WP139: MRI Evaluation and Functional Assessment of Brain Injury Improvement After 3K3A-Activated Protein C Treatment for Murine White Matter Stroke

Abstract

Introduction: Subcortical white matter stroke (WMS) accounts for 25% of all incidences of stroke and results in severe motor and cognitive disability. WMS stands as the second leading cause of dementia and is notably prevalent in older adults. Activated protein C (APC), a plasma serine protease with potent antithrombotic and cell-signaling activities, was engineered to reduce bleeding risk while retaining normal cell-signaling activities (anti-inflammatory, anti-apoptotic, and neuroregenerative, etc. activities). The engineered variant, 3K3A-APC, is neuroprotective in preclinical models of ischemic stroke with large infarcts involving common large arteries and gray matter. A multicenter Phase 2 randomized clinical trial enrolled 110 patients to assess the safety, pharmacokinetics, and efficacy of human recombinant 3K3A-APC in acute ischemic stroke patients following endovascular treatments (NCT02222714). Methods: In this new study, a murine WMS was induced by the vasoconstrictor N5-(1-iminoethyl)-L-ornithine, dihydrochloride (L-Nio) by injection into the subcortical white matter ventral to the mouse forelimb motor cortex using the Neurostar motorized ultra-precise small animal stereotaxic instrument. Mice received intravenously 0.2 mg/kg recombinant murine 3K3A-APC or saline at 4, 24, 48 and 72 h after L-Nio. Then MRI scans were performed using a 7T PET/MRI scanner (MR Solutions) and a standard quadrature coil at 1 and 7 days after the stroke. Results: Both MRI and histological results showed that 3K3A-APC significantly reduced the lesion volume, increased the viability of oligodendrocytes and neurons, and protected against blood brain barrier damage at 1 and 7 days after stroke. Behavioral tests showed that 3K3A-APC improved functional recovery. Conclusions: These results demonstrated that 3K3A-APC might be an effective treatment for white matter stroke.