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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.

SUBMITTER: Koval ED

PROVIDER: S-EPMC3781640 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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

Koval Erica D ED Shaner Carey C Zhang Peter P du Maine Xavier X Fischer Kimberlee K Tay Jia J Chau B Nelson BN Wu Gregory F GF Miller Timothy M TM

Human molecular genetics 20130604 20

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 ...[more]

PMID: 23740943

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

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

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