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Physiol Genomics. 2018 Jun 8. doi: 10.1152/physiolgenomics.00134.2017. [Epub ahead of print]

Muscle miRNAome shows suppression of chronic inflammatory miRNAs with both prednisone and vamorolone.

Author information

1
Center for Genetic Medicine Research, Children's National Medical Center, United States.
2
Center for Genetic Medicine Research, Children's National Medical Center.
3
Children's National Medical Center.
4
Department of Pharmaceutical Sciences, Binghamton University, School of Pharmacy and Pharmaceutical Sciences.

Abstract

Corticosteroids are highly prescribed and effective anti-inflammatory drugs, but the burden of side effects with chronic use significantly detracts from patient quality of life, particularly in children. Developing safer steroids amenable to long-term use is an important goal for treatment of chronic inflammatory diseases such as Duchenne muscular dystrophy (DMD). We have developed vamorolone (VBP15), a first-in-class dissociative glucocorticoid receptor (GR) ligand that shows the anti-inflammatory efficacy of corticosteroids without key steroid side effects in animal models. miRNAs are increasingly recognized as key regulators of inflammatory responses. To define effects of prednisolone and vamorolone on the muscle miRNAome, we performed a pre-clinical discovery study in the mdx mouse model of DMD. miRNAs associated with inflammation were highly elevated in mdx muscle. Both vamorolone and prednisolone returned these towards wild-type levels (miR-142-5p, miR-142-3p, miR-146a, miR-301a, miR-324-3p, miR-455-5p, miR-455-3p, miR-497, miR-652). Effects of vamorolone were largely limited to reduction of pro-inflammatory miRNAs. In contrast, prednisolone activated a separate group of miRNAs associated with steroid side effects and a non-coding RNA cluster homologous to human chromosome 14q32. Effects were validated for inflammatory miRNAs in a second, independent preclinical study. For the anti-inflammatory miRNA signature, bioinformatic analyses showed all of these miRNAs are directly regulated by, or in turn activate, the inflammatory transcription factor NF-κB. Moving forward miR-146a and miR-142-5p are of particular interest as biomarkers or novel drug targets. This data validates NF-κB signaling as a target of dissociative GR-ligand efficacy in vivo, and provides new insight into miRNA signaling in chronic inflammation.

KEYWORDS:

Duchenne Muscular Dystrophy; inflammation; miRNA; muscle; steroids

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