VBP15, a novel anti-inflammatory and membrane-stabilizer, improves muscular dystrophy without side effects
Christopher R. Heier,Jesse M. Damsker,Qing Yu,Blythe C. Dillingham,Tony Huynh,Jack H. Van der Meulen,Arpana Sali,Brittany K. Miller,Aditi Phadke,Luana Scheffer,James L Quinn,Kathleen Tatem,Sarah Jordan,Sherry Dadgar,Olga Rodriguez,Chris Albanese,Michael E. Calhoun,Heather Gordish-Dressman,Jyoti K. Jaiswal,Edward M. Connor,John M. McCall,Eric P. Hoffman,Erica K.M. Reeves,Kanneboyina Nagaraju +23 more
TLDR
Successful improvement of dystrophy independent of hormonal, growth, or immunosuppressive effects is demonstrated, indicating VBP15 merits clinical investigation for DMD and would benefit other chronic inflammatory diseases.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.read more
Citations
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Journal ArticleDOI
Duchenne muscular dystrophy.
TL;DR: In this article, the authors present guidelines for the multidisciplinary care for Duchenne muscular dystrophy that address obtaining a genetic diagnosis and managing the various aspects of the disease.
Journal ArticleDOI
The Pathogenesis and Therapy of Muscular Dystrophies
Simon Guiraud,Annemieke Aartsma-Rus,Natássia M. Vieira,Kay E. Davies,Gert-Jan B. van Ommen,Louis M. Kunkel +5 more
TL;DR: The nearly 30 years of research partly outlined here exemplifies the road that similar current gene discovery protocols will be expected to travel, albeit much more rapidly owing to improved diagnosis of genetic disorders and an understanding of the spectrum of mutations thought to cause them.
Journal ArticleDOI
Large-scale serum protein biomarker discovery in Duchenne muscular dystrophy
Yetrib Hathout,Edward N. Brody,Paula R. Clemens,Paula R. Clemens,Linda H. Cripe,Robert Kirk DeLisle,Pat Furlong,Heather Gordish-Dressman,Lauren P. Hache,Erik K Henricson,Eric P. Hoffman,Yvonne M. Kobayashi,Angela Lorts,Jean K. Mah,Craig M. McDonald,Bob Mehler,Sally K. Nelson,Malti Nikrad,Britta Singer,Fintan Steele,David Sterling,H. Lee Sweeney,Steve C.R. Williams,Larry Gold +23 more
TL;DR: A proteomics approach was described to determine serum levels of 1,125 proteins in 93 DMD patients and 45 controls and identified 44 biomarkers that differed significantly between patients and controls, demonstrating both the utility of this unbiased biomarker discovery approach and suggesting potential new diagnostic and therapeutic avenues for ameliorating the burden of DMD and, it is hoped, other rare and devastating diseases.
Journal ArticleDOI
Immune-mediated pathology in Duchenne muscular dystrophy
Amy S. Rosenberg,Montserrat Puig,Kanneboyina Nagaraju,Eric P. Hoffman,S. Armando Villalta,V. Ashutosh Rao,Lalage M. Wakefield,Janet Woodcock +7 more
TL;DR: The role of the inflammatory response in DMD pathogenesis and opportunities for clinical intervention are focused on.
Journal ArticleDOI
Duchenne Muscular Dystrophy: From Diagnosis to Therapy
TL;DR: Duchenne muscular dystrophy is an X-linked inherited neuromuscular disorder due to mutations in the dystrophin gene, which has opened novel avenues in molecular biology, medical genetics and novel therapeutic options.
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