Cargando…

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

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Eding, Joep E.C., Demkes, Charlotte J., Lynch, Joshua M., Seto, Anita G., Montgomery, Rusty L., Semus, Hillary M., Jackson, Aimee L., Isabelle, Marc, Chimenti, Stefano, van Rooij, Eva
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5363185/
https://www.ncbi.nlm.nih.gov/pubmed/28202391
http://dx.doi.org/10.1016/j.ymthe.2017.01.012
_version_ 1782517125689114624
author Eding, Joep E.C.
Demkes, Charlotte J.
Lynch, Joshua M.
Seto, Anita G.
Montgomery, Rusty L.
Semus, Hillary M.
Jackson, Aimee L.
Isabelle, Marc
Chimenti, Stefano
van Rooij, Eva
author_facet Eding, Joep E.C.
Demkes, Charlotte J.
Lynch, Joshua M.
Seto, Anita G.
Montgomery, Rusty L.
Semus, Hillary M.
Jackson, Aimee L.
Isabelle, Marc
Chimenti, Stefano
van Rooij, Eva
author_sort Eding, Joep E.C.
collection PubMed
description 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.
format Online
Article
Text
id pubmed-5363185
institution National Center for Biotechnology Information
language English
publishDate 2017
publisher American Society of Gene & Cell Therapy
record_format MEDLINE/PubMed
spelling pubmed-53631852018-03-01 The Efficacy of Cardiac Anti-miR-208a Therapy Is Stress Dependent Eding, Joep E.C. Demkes, Charlotte J. Lynch, Joshua M. Seto, Anita G. Montgomery, Rusty L. Semus, Hillary M. Jackson, Aimee L. Isabelle, Marc Chimenti, Stefano van Rooij, Eva Mol Ther Original Article 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. American Society of Gene & Cell Therapy 2017-03-01 2017-02-12 /pmc/articles/PMC5363185/ /pubmed/28202391 http://dx.doi.org/10.1016/j.ymthe.2017.01.012 Text en © 2017 The Author(s) http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Original Article
Eding, Joep E.C.
Demkes, Charlotte J.
Lynch, Joshua M.
Seto, Anita G.
Montgomery, Rusty L.
Semus, Hillary M.
Jackson, Aimee L.
Isabelle, Marc
Chimenti, Stefano
van Rooij, Eva
The Efficacy of Cardiac Anti-miR-208a Therapy Is Stress Dependent
title The Efficacy of Cardiac Anti-miR-208a Therapy Is Stress Dependent
title_full The Efficacy of Cardiac Anti-miR-208a Therapy Is Stress Dependent
title_fullStr The Efficacy of Cardiac Anti-miR-208a Therapy Is Stress Dependent
title_full_unstemmed The Efficacy of Cardiac Anti-miR-208a Therapy Is Stress Dependent
title_short The Efficacy of Cardiac Anti-miR-208a Therapy Is Stress Dependent
title_sort efficacy of cardiac anti-mir-208a therapy is stress dependent
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5363185/
https://www.ncbi.nlm.nih.gov/pubmed/28202391
http://dx.doi.org/10.1016/j.ymthe.2017.01.012
work_keys_str_mv AT edingjoepec theefficacyofcardiacantimir208atherapyisstressdependent
AT demkescharlottej theefficacyofcardiacantimir208atherapyisstressdependent
AT lynchjoshuam theefficacyofcardiacantimir208atherapyisstressdependent
AT setoanitag theefficacyofcardiacantimir208atherapyisstressdependent
AT montgomeryrustyl theefficacyofcardiacantimir208atherapyisstressdependent
AT semushillarym theefficacyofcardiacantimir208atherapyisstressdependent
AT jacksonaimeel theefficacyofcardiacantimir208atherapyisstressdependent
AT isabellemarc theefficacyofcardiacantimir208atherapyisstressdependent
AT chimentistefano theefficacyofcardiacantimir208atherapyisstressdependent
AT vanrooijeva theefficacyofcardiacantimir208atherapyisstressdependent
AT edingjoepec efficacyofcardiacantimir208atherapyisstressdependent
AT demkescharlottej efficacyofcardiacantimir208atherapyisstressdependent
AT lynchjoshuam efficacyofcardiacantimir208atherapyisstressdependent
AT setoanitag efficacyofcardiacantimir208atherapyisstressdependent
AT montgomeryrustyl efficacyofcardiacantimir208atherapyisstressdependent
AT semushillarym efficacyofcardiacantimir208atherapyisstressdependent
AT jacksonaimeel efficacyofcardiacantimir208atherapyisstressdependent
AT isabellemarc efficacyofcardiacantimir208atherapyisstressdependent
AT chimentistefano efficacyofcardiacantimir208atherapyisstressdependent
AT vanrooijeva efficacyofcardiacantimir208atherapyisstressdependent