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

EMBO Molecular Medicine

Christopher R. Heier¹  Jesse M. Damsker³  Qing Yu¹  Blythe C. Dillingham¹  Tony Huynh¹  Jack H. Van der Meulen¹  Arpana Sali¹  Brittany K. Miller¹  Aditi Phadke¹  Luana Scheffer¹  James Quinn¹  Kathleen Tatem¹  Sarah Jordan¹  Sherry Dadgar¹  Olga C. Rodriguez⁴  Chris Albanese⁴  Michael Calhoun²  Heather Gordish-Dressman¹  Jyoti K. Jaiswal¹  Edward M. Connor¹  John M. McCall³  Eric P. Hoffman¹  Erica K. M. Reeves³ 

[1] Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC, USA;Sinq Systems, Silver Spring, MD, USA;ReveraGen BioPharma, Rockville, MD, USA;Lombardi Comprehensive Cancer Center and Department of Oncology, Georgetown University Medical Center, Washington, DC, USA

关键词: anti‐inflammatory;    dystrophy;    mdx;    membrane injury;    muscle;   

DOI  :  10.1002/emmm.201302621

来源: Wiley

【 摘 要 】

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.

【 授权许可】

CC BY   
Copyright © 2013 EMBO Molecular Medicine

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