Disease-modifying effects of orally bioavailable NF-κB inhibitors in dystrophin-deficient muscle
David W. Hammers, … , Glenn A. Walter, H. Lee Sweeney
David W. Hammers, … , Glenn A. Walter, H. Lee Sweeney
Published December 22, 2016
Citation Information: JCI Insight. 2016;1(21):e90341. https://doi.org/10.1172/jci.insight.90341.
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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 7

Dysferlin content is increased in CAT-1041–treated mdx mice.

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Dysferlin content is increased in CAT-1041–treated mdx mice. (A) Represe...
(A) Representative immunoblots and (B) quantifications of utrophin, integrin α7, and integrin β1 in the quadriceps lysates from mdx mice fed either control (n = 7) or CAT-1041–containing chow (n = 6) and provided in-cage voluntary running wheels for 25 weeks. (C) Representative immunoblots and (D) quantifications of full-length dysferlin, as detected with both Romeo (N-terminal) and Hamlet (C-terminal) antibodies, and the C72 dysferlin cleavage product, as detected with Hamlet antibody. Protein contents are normalized to Ponceau red–visualized loading. Gene expression of total Dysf and isoforms containing the canonical C2A isoform, C2A variant 1 (C2Av1), and exon 40a in the quadriceps of untreated (n = 4) and CAT-1041–treated (n = 4) mdx mice, using Gapdh as the ΔΔCt normalization gene. (F) Immunofluorescence (IF) staining for N-terminal dysferlin in stabilized regions of untreated and CAT-1041–treated quadriceps cross sections acquired under identical conditions. Scale bar: 100 μm. 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.