title: 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.
authors.affiliation: Hubrecht Institute, KNAW and University Medical Center Utrecht, 3584CT Utrecht, the Netherlands.
authors.forename: Joep E C
authors.initials: JE
authors.lastname: Eding
authors.affiliation: Hubrecht Institute, KNAW and University Medical Center Utrecht, 3584CT Utrecht, the Netherlands; Department of Cardiology, University Medical Center Utrecht, 3584CT Utrecht, the Netherlands.
authors.forename: Charlotte J
authors.initials: CJ
authors.lastname: Demkes
authors.affiliation: miRagen Therapeutics, Inc., Boulder, CO 80301, USA.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Lynch
authors.affiliation: miRagen Therapeutics, Inc., Boulder, CO 80301, USA.
authors.forename: Anita G
authors.initials: AG
authors.lastname: Seto
authors.affiliation: miRagen Therapeutics, Inc., Boulder, CO 80301, USA.
authors.forename: Rusty L
authors.initials: RL
authors.lastname: Montgomery
authors.affiliation: Department of Cardiology, University Medical Center Utrecht, 3584CT Utrecht, the Netherlands.
authors.forename: Hillary M
authors.initials: HM
authors.lastname: Semus
authors.affiliation: miRagen Therapeutics, Inc., Boulder, CO 80301, USA.
authors.forename: Aimee L
authors.initials: AL
authors.lastname: Jackson
authors.affiliation: Servier Research Institute, Suresnes 92150, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Isabelle
authors.affiliation: Servier Research Institute, Suresnes 92150, France.
authors.forename: Stefano
authors.initials: S
authors.lastname: Chimenti
authors.affiliation: Hubrecht Institute, KNAW and University Medical Center Utrecht, 3584CT Utrecht, the Netherlands; Department of Cardiology, University Medical Center Utrecht, 3584CT Utrecht, the Netherlands. Electronic address: e.vanrooij@hubrecht.eu.
authors.forename: Eva
authors.initials: E
authors.lastname: van Rooij
mesh_terms: D000818:Animals; D000070416:Antagomirs / Q000235:genetics*; D002478:Cells, Cultured; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000378:metabolism*; D034622:RNA Interference; D051381:Rats; D013312:Stress, Physiological / Q000235:genetics*; D013552:Swine
chemical_list: D000070416:Antagomirs; C569395:MIRN208 microRNA, rat; D035683:MicroRNAs
keywords: anti-miR; microRNA; target