Disease-modifying effects of orally bioavailable NF-κB inhibitors in dystrophin-deficient muscle
David W. Hammers, Margaret M. Sleeper, Sean C. Forbes, Cora C. Coker, Michael R. Jirousek, Michael Zimmer, Glenn A. Walter, H. Lee Sweeney
David W. Hammers, Margaret M. Sleeper, Sean C. Forbes, Cora C. Coker, Michael R. Jirousek, Michael Zimmer, Glenn A. Walter, H. Lee Sweeney
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Research Article Inflammation Muscle biology

Disease-modifying effects of orally bioavailable NF-κB inhibitors in dystrophin-deficient muscle

Abstract

Duchenne muscular dystrophy (DMD) is a devastating muscle disease characterized by progressive muscle deterioration and replacement with an aberrant fatty, fibrous matrix. Chronic upregulation of nuclear factor κB (NF-κB) is implicated as a driver of the dystrophic pathogenesis. Herein, 2 members of a novel class of NF-κB inhibitors, edasalonexent (formerly CAT-1004) and CAT-1041, were evaluated in both mdx mouse and golden retriever muscular dystrophy (GRMD) dog models of DMD. These orally bioavailable compounds consist of a polyunsaturated fatty acid conjugated to salicylic acid and potently suppress the pathogenic NF-κB subunit p65/RelA in vitro. In vivo, CAT-1041 effectively improved the phenotype of mdx mice undergoing voluntary wheel running, in terms of activity, muscle mass and function, damage, inflammation, fibrosis, and cardiac pathology. We identified significant increases in dysferlin as a possible contributor to the protective effect of CAT-1041 to sarcolemmal damage. Furthermore, CAT-1041 improved the more severe GRMD phenotype in a canine case study, where muscle mass and diaphragm function were maintained in a treated GRMD dog. These results demonstrate that NF-κB modulation by edasalonexent and CAT-1041 is effective in ameliorating the dystrophic process and these compounds are candidates for new treatments for DMD patients.

Authors

David W. Hammers, Margaret M. Sleeper, Sean C. Forbes, Cora C. Coker, Michael R. Jirousek, Michael Zimmer, Glenn A. Walter, H. Lee Sweeney

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Figure 5

Phenotype of mdx muscle is improved by CAT-1041 treatment.

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Phenotype of mdx muscle is improved by CAT-1041 treatment. Dystrophic md...
Dystrophic mdx mice fed either control (n = 7) or CAT-1041–containing chow (n = 6) were provided in-cage voluntary running wheels for 25 weeks. (A) Representative images of Masson’s trichrome staining and (B) accompanying quantification of intramuscular fibrosis of the quadriceps, extensor digitorum longus (EDL), and diaphragm as performed using 5 independent fields of view for each sample. (C) Muscle damage to the quadriceps was visualized by immunofluorescence (IF) staining muscle cross sections for laminin and endogenous mouse IgGs to label serum-permeable muscle fibers. The dotted lines demonstrate labeling of damaged fibers, which was (D) quantified as percentage of total area using 4 independent fields of view for each sample. Scale bars: 100 μm. Immunoblot quantifications for (E) NF-κB components and (F) markers of inflammation, including osteopontin (OPN), IL-6, IL-4, and matrix metalloproteinase (MMP) 2, and fibrosis, including fibroblast-specific protein 1 (FSP-1) and fibronectin (Fn), as measured by immunoblotting. Protein contents are normalized to Ponceau red–visualized loading. Data are displayed as box-and-whisker plots, indicating first and third quartiles, median, minimum, and maximum values, and were analyzed using 2-tailed Welch’s t test with effect size displayed as Cohen’s d.