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 3

Edasalonexent and CAT-1041 are potent NF-κB inhibitors.

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Edasalonexent and CAT-1041 are potent NF-κB inhibitors. (A) Chemical str...
(A) Chemical structures of edasalonexent (aka CAT-1004) and CAT-1041. (B) Edasalonexent and (C) CAT-1041 inhibit LPS-induced p65-dependent transcriptional activity in RAW 264 cells (mouse macrophage cell line). (D) CAT-1041 inhibits LPS- and TNF-α–stimulated p65 binding in human peripheral blood mononuclear cells. Data are displayed as box-and-whisker plots, indicating first and third quartiles, median, minimum, and maximum values. *P < 0.05, ***P < 0.001, ****P < 0.0001 for respective comparisons. (E) The treatment of mdx mice with either CAT-1041 or edasalonexent for 20 weeks results in reduced susceptibility of the extensor digitorum longus muscle to eccentric contraction–induced injury. Values are indicated as mean ± SEM; contraction-matched values not connected by a letter are significantly different by Tukey honest significant difference post-hoc test (α = 0.05).