Method for widespread microRNA-155 inhibition prolongs survival in ALS-model mice

Hum Mol Genet. 2013 Oct 15;22(20):4127-35. doi: 10.1093/hmg/ddt261. Epub 2013 Jun 4.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Amyotrophic Lateral Sclerosis / drug therapy*
  • Amyotrophic Lateral Sclerosis / genetics*
  • Amyotrophic Lateral Sclerosis / metabolism
  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • Case-Control Studies
  • Disease Models, Animal
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs / antagonists & inhibitors*
  • MicroRNAs / genetics
  • Middle Aged
  • Molecular Targeted Therapy
  • Oligonucleotides, Antisense / metabolism
  • Oligonucleotides, Antisense / therapeutic use*
  • Rats
  • Spinal Cord / drug effects
  • Spinal Cord / metabolism
  • Superoxide Dismutase / genetics


  • MIRN155 microRNA, human
  • MIRN155 microRNA, rat
  • MicroRNAs
  • Mirn155 microRNA, mouse
  • Oligonucleotides, Antisense
  • SOD1 G93A protein
  • Superoxide Dismutase