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

Koval ED, Shaner C, Zhang P, Du Maine X, Fischer K, Tay J, Nelson Chau B, Wu GF, Miller TM; (2013) Human Molecular Genetics, 22 (20), art. no. ddt261, pp. 4127-4135 Read More


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 inhibitmiRNAs 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 spinalcord. After treating SOD1G93A mice with anti-miR-155, we significantly extended survival by 10 daysand 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.

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Posted on October 8, 2013
Posted in: Axon Injury & Repair, HPAN, Publications Authors: ,