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

TY - JOUR

T1 - The Efficacy of Cardiac Anti-miR-208a Therapy Is Stress Dependent

AU - Eding, Joep E C

AU - Demkes, Charlotte J

AU - Lynch, Joshua M

AU - Seto, Anita G

AU - Montgomery, Rusty L

AU - Semus, Hillary M

AU - Jackson, Aimee L

AU - Isabelle, Marc

AU - Chimenti, Stefano

AU - van Rooij, Eva

N1 - Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

PY - 2017/3/1

Y1 - 2017/3/1

N2 - 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.

AB - 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.

KW - Animals

KW - Antagomirs

KW - Cells, Cultured

KW - Gene Expression Profiling

KW - Gene Expression Regulation

KW - Male

KW - MicroRNAs

KW - Myocytes, Cardiac

KW - RNA Interference

KW - Rats

KW - Stress, Physiological

KW - Swine

KW - Journal Article

U2 - 10.1016/j.ymthe.2017.01.012

DO - 10.1016/j.ymthe.2017.01.012

M3 - Article

C2 - 28202391

SN - 1525-0016

VL - 25

SP - 694

EP - 704

JO - Molecular Therapy

JF - Molecular Therapy

IS - 3

ER -