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The Efficacy of Cardiac Anti-miR-208a Therapy Is Stress Dependent.

ABSTRACT: MicroRNAs (miRNAs) are important regulators of biology and disease. Recent animal efficacy studies validate the therapeutic benefit of miRNA modulation and underscore the therapeutic value of miRNA-targeting oligonucleotides. However, whether disease conditions (stress) influence the pharmacological effects of an anti-miR is currently unknown. To study the effect of disease on target regulation after anti-miR treatment, we injected animals with anti-miR-208a, a synthetic oligonucleotide that inhibits the cardiomyocyte-specific miR-208a. Our data indicate that the presence of stress increases the number of regulated miR-208a targets, and that higher stress levels correlate with stronger target derepression. Additionally, the type of stress also influences which targets are regulated upon miR-208a inhibition. Studies in a large animal model indicate a similar stress-dependent anti-miR effect. Subsequent in vitro studies suggest that the influence of stress on anti-miR efficacy depends at least in part on increased cellular anti-miR uptake. These data indicate that the pharmacological effect of anti-miRs is stronger under disease conditions, and that both the type and severity of disease determine the therapeutic outcome. These facts will be important for assessing the therapeutic dose and predicting the therapeutic outcome when applying anti-miRs in a clinical setting.

SUBMITTER: Eding JE

PROVIDER: S-EPMC5363185 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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The Efficacy of Cardiac Anti-miR-208a Therapy Is Stress Dependent.

Eding Joep E C JE Demkes Charlotte J CJ Lynch Joshua M JM Seto Anita G AG Montgomery Rusty L RL Semus Hillary M HM Jackson Aimee L AL Isabelle Marc M Chimenti Stefano S van Rooij Eva E

Molecular therapy : the journal of the American Society of Gene Therapy 20170212 3

MicroRNAs (miRNAs) are important regulators of biology and disease. Recent animal efficacy studies validate the therapeutic benefit of miRNA modulation and underscore the therapeutic value of miRNA-targeting oligonucleotides. However, whether disease conditions (stress) influence the pharmacological effects of an anti-miR is currently unknown. To study the effect of disease on target regulation after anti-miR treatment, we injected animals with anti-miR-208a, a synthetic oligonucleotide that inh ...[more]

PMID: 28202391

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The Efficacy of Cardiac Anti-miR-208a Therapy Is Stress Dependent.

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The Efficacy of Cardiac Anti-miR-208a Therapy Is Stress Dependent.

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