title: VBP15, a novel anti-inflammatory and membrane-stabilizer, improves muscular dystrophy without side effects.
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.
authors.affiliation: Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC, USA.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Heier
authors.forename: Jesse M
authors.initials: JM
authors.lastname: Damsker
authors.forename: Qing
authors.initials: Q
authors.lastname: Yu
authors.forename: Blythe C
authors.initials: BC
authors.lastname: Dillingham
authors.forename: Tony
authors.initials: T
authors.lastname: Huynh
authors.forename: Jack H
authors.initials: JH
authors.lastname: Van der Meulen
authors.forename: Arpana
authors.initials: A
authors.lastname: Sali
authors.forename: Brittany K
authors.initials: BK
authors.lastname: Miller
authors.forename: Aditi
authors.initials: A
authors.lastname: Phadke
authors.forename: Luana
authors.initials: L
authors.lastname: Scheffer
authors.forename: James
authors.initials: J
authors.lastname: Quinn
authors.forename: Kathleen
authors.initials: K
authors.lastname: Tatem
authors.forename: Sarah
authors.initials: S
authors.lastname: Jordan
authors.forename: Sherry
authors.initials: S
authors.lastname: Dadgar
authors.forename: Olga C
authors.initials: OC
authors.lastname: Rodriguez
authors.forename: Chris
authors.initials: C
authors.lastname: Albanese
authors.forename: Michael
authors.initials: M
authors.lastname: Calhoun
authors.forename: Heather
authors.initials: H
authors.lastname: Gordish-Dressman
authors.forename: Jyoti K
authors.initials: JK
authors.lastname: Jaiswal
authors.forename: Edward M
authors.initials: EM
authors.lastname: Connor
authors.forename: John M
authors.initials: JM
authors.lastname: McCall
authors.forename: Eric P
authors.initials: EP
authors.lastname: Hoffman
authors.forename: Erica K M
authors.initials: EK
authors.lastname: Reeves
authors.forename: Kanneboyina
authors.initials: K
authors.lastname: Nagaraju
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000633:toxicity; D007834:Lasers; D051379:Mice; D018101:Mice, Inbred mdx; D009136:Muscular Dystrophies / Q000378:metabolism / Q000473:pathology; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects* / Q000528:radiation effects; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009336:Necrosis / Q000209:etiology; D010641:Phenotype; D011239:Prednisolone / Q000494:pharmacology / Q000633:toxicity; D011244:Pregnadienediols / Q000494:pharmacology* / Q000633:toxicity; D060066:Protein Interaction Maps / Q000187:drug effects; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D000893:Anti-Inflammatory Agents; D007166:Immunosuppressive Agents; D016328:NF-kappa B; D011244:Pregnadienediols; D011965:Receptors, Glucocorticoid; C584811:VBP15 compound; D011239:Prednisolone
keywords: anti-inflammatory; dystrophy; mdx; membrane injury; muscle