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 9

GRMD phenotype is improved by CAT-1041 in a canine case study.

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GRMD phenotype is improved by CAT-1041 in a canine case study. An affect...
An affected golden retriever muscular dystrophy (GRMD) dog was treated with CAT-1041 daily, starting at 3 months of age, for 9 months. (A) Serial magnetic resonance imaging (MRI) to measure the (B) muscle volume of the anterior compartment of the hind limb (consisting of the tibialis cranialis [TC] and extensor digitorum longus [EDL] muscles) in the treated and age-matched, untreated GRMD dogs (n = 3). At the end of the 9-month treatment protocol, the dogs were evaluated for ventilatory function, as measured by (C) conscious inspiratory tidal volume and (D) dynamic lung compliance (20 breaths per dog). Dotted lines indicate minimum reference values for size-matched normal dogs. (E) Representative Masson’s trichrome staining of untreated and CAT-1041–treated TC, diaphragm (Dp), and left ventricle (LV). (F) Immunohistochemical (IHC) staining of the fibroblast marker prolyl 4-hydroxylase in the TC and Dp. (G) Dp fiber size distribution and (H) N-terminal dysferlin immunofluorescence (IF) of normal, untreated GRMD, and CAT-1041–treated GRMD dogs. Scale bars: 100 μm. Data are displayed as (B) mean ± SD of left and right limbs, (C and D) box-and-whisker plots, indicating first and third quartiles, median, minimum, and maximum values of total breaths measured, or (G) percentage total muscle fiber population (n = 200–400 fibers per sample).