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.

Clinical Trial Designs in Amyotrophic Lateral Sclerosis: Does One Design Fit All?

“…Regulatory T cells, which are reduced in patients with rapidly progressive ALS, may be a predictive marker [37,38]. miR-155 (i.e., micro-RNA), a promising marker of inflammation, is found to be upregulated in patients with ALS and may be predictive or prognostic [39][40][41]. These efforts will require concerted effort and considerable resources, but, if successful, will represent important new tools to speed ALS therapy development.…”

Current developments in gene therapy for amyotrophic lateral sclerosis

“…In 2013 it was reported that endogenous miRNA-155 is significantly upregulated in the spinal cord tissue of both ALS rodent models and human ALS patients [78,79]. In this study, specific ASOs designed to decrease the levels of miRNA-155 in SOD1-G93A mice prolonged survival in this murine model in comparison to scrambled control antimiRNA [78].…”

miR-155 Is Essential for Inflammation-Induced Hippocampal Neurogenic Dysfunction

“…Proinflammatory stimuli upregulate miR-155 and miR-155 represses anti-inflammatory molecules (Cardoso et al, 2012;Elton et al, 2013). miR-155 is increased in inflammatory CNS disorders, including human ex vivo specimens and animal models of amyotrophic lateral sclerosis (ALS) (Koval et al, 2013), multiple sclerosis (MS) (Junker, 2011;Murugaiyan et al, 2011;Moore et al, 2013), and Down syndrome (Keck-Wherley et al, 2011;Wang et al, 2013). Importantly, targeting miR-155 is beneficial in animal models of MS and ALS (Butovsky et al, 2015).…”