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Research Article
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Vamorolone targets dual nuclear receptors to treat inflammation and dystrophic cardiomyopathy

View ORCID ProfileChristopher R Heier  Correspondence email, Qing Yu, Alyson A Fiorillo, Christopher B Tully, Asya Tucker, Davi A Mazala, Kitipong Uaesoontrachoon, Sadish Srinivassane, Jesse M Damsker, Eric P Hoffman, Kanneboyina Nagaraju, Christopher F Spurney
Christopher R Heier
1Department of Genomics and Precision Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, USA
2Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC, USA
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  • ORCID record for Christopher R Heier
  • For correspondence: cheier@childrensnational.org
Qing Yu
2Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC, USA
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Alyson A Fiorillo
1Department of Genomics and Precision Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, USA
2Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC, USA
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Christopher B Tully
2Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC, USA
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Asya Tucker
2Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC, USA
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Davi A Mazala
2Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC, USA
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Kitipong Uaesoontrachoon
3AGADA Biosciences Incorporated, Halifax, Nova Scotia, Canada
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Sadish Srinivassane
3AGADA Biosciences Incorporated, Halifax, Nova Scotia, Canada
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Jesse M Damsker
4ReveraGen BioPharma, Incorporated, Rockville, MD, USA
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Eric P Hoffman
3AGADA Biosciences Incorporated, Halifax, Nova Scotia, Canada
4ReveraGen BioPharma, Incorporated, Rockville, MD, USA
5School of Pharmacy and Pharmaceutical Sciences, Binghamton University—State University of New York (SUNY), Binghamton, NY, USA
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Kanneboyina Nagaraju
3AGADA Biosciences Incorporated, Halifax, Nova Scotia, Canada
4ReveraGen BioPharma, Incorporated, Rockville, MD, USA
5School of Pharmacy and Pharmaceutical Sciences, Binghamton University—State University of New York (SUNY), Binghamton, NY, USA
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Christopher F Spurney
1Department of Genomics and Precision Medicine, George Washington University School of Medicine and Health Sciences, Washington, DC, USA
2Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC, USA
6Division of Cardiology, Children's National Heart Institute, Children's National Medical Center, Washington, DC, USA
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Published 11 February 2019. DOI: 10.26508/lsa.201800186
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Abstract

Cardiomyopathy is a leading cause of death for Duchenne muscular dystrophy. Here, we find that the mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) can share common ligands but play distinct roles in dystrophic heart and skeletal muscle pathophysiology. Comparisons of their ligand structures indicate that the Δ9,11 modification of the first-in-class drug vamorolone enables it to avoid interaction with a conserved receptor residue (N770/N564), which would otherwise activate transcription factor properties of both receptors. Reporter assays show that vamorolone and eplerenone are MR antagonists, whereas prednisolone is an MR agonist. Macrophages, cardiomyocytes, and CRISPR knockout myoblasts show vamorolone is also a dissociative GR ligand that inhibits inflammation with improved safety over prednisone and GR-specific deflazacort. In mice, hyperaldosteronism activates MR-driven hypertension and kidney phenotypes. We find that genetic dystrophin loss provides a second hit for MR-mediated cardiomyopathy in Duchenne muscular dystrophy model mice, as aldosterone worsens fibrosis, mass and dysfunction phenotypes. Vamorolone successfully prevents MR-activated phenotypes, whereas prednisolone activates negative MR and GR effects. In conclusion, vamorolone targets dual nuclear receptors to treat inflammation and cardiomyopathy with improved safety.

  • Received August 29, 2018.
  • Revision received January 25, 2019.
  • Accepted January 28, 2019.
  • © 2019 Heier et al.
Creative Commons logoCreative Commons logohttps://creativecommons.org/licenses/by/4.0/

This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).

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Effects of nuclear receptor ligands in DMD
Christopher R Heier, Qing Yu, Alyson A Fiorillo, Christopher B Tully, Asya Tucker, Davi A Mazala, Kitipong Uaesoontrachoon, Sadish Srinivassane, Jesse M Damsker, Eric P Hoffman, Kanneboyina Nagaraju, Christopher F Spurney
Life Science Alliance Feb 2019, 2 (1) e201800186; DOI: 10.26508/lsa.201800186

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Effects of nuclear receptor ligands in DMD
Christopher R Heier, Qing Yu, Alyson A Fiorillo, Christopher B Tully, Asya Tucker, Davi A Mazala, Kitipong Uaesoontrachoon, Sadish Srinivassane, Jesse M Damsker, Eric P Hoffman, Kanneboyina Nagaraju, Christopher F Spurney
Life Science Alliance Feb 2019, 2 (1) e201800186; DOI: 10.26508/lsa.201800186
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Volume 2, No. 1
February 2019
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