title: Method for widespread microRNA-155 inhibition prolongs survival in ALS-model mice.
abstract: microRNAs (miRNAs) are dysregulated in a variety of disease states, suggesting that this newly discovered class of gene expression repressors may be viable therapeutic targets. A microarray of miRNA changes in ALS-model superoxide dismutase 1 (SOD1)(G93A) rodents identified 12 miRNAs as significantly changed. Six miRNAs tested in human ALS tissues were confirmed increased. Specifically, miR-155 was increased 5-fold in mice and 2-fold in human spinal cords. To test miRNA inhibition in the central nervous system (CNS) as a potential novel therapeutic, we developed oligonucleotide-based miRNA inhibitors (anti-miRs) that could inhibit miRNAs throughout the CNS and in the periphery. Anti-miR-155 caused global derepression of targets in peritoneal macrophages and, following intraventricular delivery, demonstrated widespread functional distribution in the brain and spinal cord. After treating SOD1(G93A) mice with anti-miR-155, we significantly extended survival by 10 days and disease duration by 15 days (38%) while a scrambled control anti-miR did not significantly improve survival or disease duration. Therefore, antisense oligonucleotides may be used to successfully inhibit miRNAs throughout the brain and spinal cord, and miR-155 is a promising new therapeutic target for human ALS.
authors.forename: Erica D
authors.initials: ED
authors.lastname: Koval
authors.forename: Carey
authors.initials: C
authors.lastname: Shaner
authors.forename: Peter
authors.initials: P
authors.lastname: Zhang
authors.forename: Xavier
authors.initials: X
authors.lastname: du Maine
authors.forename: Kimberlee
authors.initials: K
authors.lastname: Fischer
authors.forename: Jia
authors.initials: J
authors.lastname: Tay
authors.forename: B Nelson
authors.initials: BN
authors.lastname: Chau
authors.forename: Gregory F
authors.initials: GF
authors.lastname: Wu
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Miller
mesh_terms: D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016022:Case-Control Studies; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000037:antagonists & inhibitors* / Q000235:genetics; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D016376:Oligonucleotides, Antisense / Q000378:metabolism / Q000627:therapeutic use*; D051381:Rats; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics
chemical_list: C524942:MIRN155 microRNA, human; C580597:MIRN155 microRNA, rat; D035683:MicroRNAs; C532623:Mirn155 microRNA, mouse; D016376:Oligonucleotides, Antisense; C109415:SOD1 G93A protein; D013482:Superoxide Dismutase