VBP15, a novel anti-inflammatory and membrane-stabilizer, improves muscular dystrophy without side effects

Authors

  • Christopher R. Heier,

    1. Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC, USA
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  • Jesse M. Damsker,

    1. ReveraGen BioPharma, Rockville, MD, USA
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  • Qing Yu,

    1. Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC, USA
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  • Blythe C. Dillingham,

    1. Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC, USA
    2. ReveraGen BioPharma, Rockville, MD, USA
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  • Tony Huynh,

    1. Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC, USA
    2. Endocrine Research Unit, The Canberra Hospital, Garran, ACT, Australia
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  • Jack H. Van der Meulen,

    1. Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC, USA
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  • Arpana Sali,

    1. Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC, USA
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  • Brittany K. Miller,

    1. Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC, USA
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  • Aditi Phadke,

    1. Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC, USA
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  • Luana Scheffer,

    1. Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC, USA
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  • James Quinn,

    1. Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC, USA
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  • Kathleen Tatem,

    1. Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC, USA
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  • Sarah Jordan,

    1. Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC, USA
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  • Sherry Dadgar,

    1. Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC, USA
    2. Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA
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  • Olga C. Rodriguez,

    1. Lombardi Comprehensive Cancer Center and Department of Oncology, Georgetown University Medical Center, Washington, DC, USA
    2. Department of Pathology, Georgetown University Medical Center, Washington, DC, USA
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  • Chris Albanese,

    1. Lombardi Comprehensive Cancer Center and Department of Oncology, Georgetown University Medical Center, Washington, DC, USA
    2. Department of Pathology, Georgetown University Medical Center, Washington, DC, USA
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  • Michael Calhoun,

    1. Sinq Systems, Silver Spring, MD, USA
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  • Heather Gordish-Dressman,

    1. Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC, USA
    2. Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA
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  • Jyoti K. Jaiswal,

    1. Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC, USA
    2. Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA
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  • Edward M. Connor,

    1. Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC, USA
    2. ReveraGen BioPharma, Rockville, MD, USA
    3. Center for Translational Science, Children's National Medical Center, Washington, DC, USA
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  • John M. McCall,

    1. ReveraGen BioPharma, Rockville, MD, USA
    2. PharMac LLC, Boca Grande, FL, USA
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  • Eric P. Hoffman,

    1. Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC, USA
    2. ReveraGen BioPharma, Rockville, MD, USA
    3. Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA
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  • Erica K. M. Reeves,

    1. ReveraGen BioPharma, Rockville, MD, USA
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  • Kanneboyina Nagaraju

    Corresponding author
    1. Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC, USA
    2. ReveraGen BioPharma, Rockville, MD, USA
    3. Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA
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Abstract

Absence of dystrophin makes skeletal muscle more susceptible to injury, resulting in breaches of the plasma membrane and chronic inflammation in Duchenne muscular dystrophy (DMD). Current management by glucocorticoids has unclear molecular benefits and harsh side effects. It is uncertain whether therapies that avoid hormonal stunting of growth and development, and/or immunosuppression, would be more or less beneficial. Here, we discover an oral drug with mechanisms that provide efficacy through anti-inflammatory signaling and membrane-stabilizing pathways, independent of hormonal or immunosuppressive effects. We find VBP15 protects and promotes efficient repair of skeletal muscle cells upon laser injury, in opposition to prednisolone. Potent inhibition of NF-κB is mediated through protein interactions of the glucocorticoid receptor, however VBP15 shows significantly reduced hormonal receptor transcriptional activity. The translation of these drug mechanisms into DMD model mice improves muscle strength, live-imaging and pathology through both preventive and post-onset intervention regimens. These data demonstrate successful improvement of dystrophy independent of hormonal, growth, or immunosuppressive effects, indicating VBP15 merits clinical investigation for DMD and would benefit other chronic inflammatory diseases.

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