Abstract WP127: Intravenous Administration of Microrna-122 Mimic for Treatment of Ischemic and Hemorrhagic Strokes in Rats

Abstract

MicroRNAs(miRs)are very promising next generation drug targets due to their unique miR-target binding that is different from the traditional ligand-receptor. A single miR binds to complementary bases in the 3’ untranslated regions(3’UTR) of hundreds of target genes and down-regulates these genes. MiR therapeutics have been developed for treatment of various diseases, with several miR drugs(e.g., miR-122/miR-155 inhibitors, miR-16/29/34 mimics) being advanced into human trials in the last decade. Our previous studies showed that intravenous (i.v.) miR-122 mimic (2.4mg/kg, wrapped in PEG-liposomes) improves outcomes after suture middle cerebral artery occlusion(MCAO)-induced ischemic stroke (IS) with a 6 hour time window. In pilot whole genome miR expression studies, we demonstrated that microRNA-122 (miR-122) is the most significantly decreased miR in blood after intraventricularautologousfresh blood-induced intracerebral hemorrhage (ICH) in rats. As compared to sham controls, miR-122 decreased 28 fold at 3 hrs, 34 fold at 24 hrs, 31 fold at 7 days and 19 fold at 14 days in blood after ICH in rats. These miRNA expression data suggest that elevating miR-122 in blood has great potential to treat ICH in addition to IS. Therefore, we hypothesized that i.v. miR-122 mimic improves outcomes after ICH, in addition to IS. Our miR-122 targetome studies show that a set of miR-122 target genes (Pla2g2a, Vcam1, Nos2, Rhbdf1, Olig1, Nrep) are responsible for the therapeutic efficacy of miR-122 mimic on ischemic stroke, while another set of genes (Ywhaq, Klrk1, Tpst1, Vars2)account for efficacy in ICH. Using3’UTR luciferase reporter assays and anti-sense Morpholino Oligos (MOs), we show that miR-122 binds to 3’UTR of its target genes Pla2g2a and Vcam1, rather than Nos2. In addition, in vivo MO-miR-122-Pla2g2a blocks miR-122 mimic treatment-induced decrease of Pla2g2a in blood cells after ischemic stroke. In summary, our data suggest miR-122 mimic can treat IS and ICH. Therefore, the miR-122 mimic treatment for IS and ICH could likely be performed without brain imaging (e.g. in the ambulance, and/or emergency room) since it is broadly efficacious for both IS and ICH.