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JCI Insight. 2016 Dec 22;1(21):e90341. doi: 10.1172/jci.insight.90341.

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

Author information

1
Department of Physiology and; Pennsylvania Muscle Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.; Department of Pharmacology and Therapeutics,; Myology Institute and.
2
Myology Institute and; Department of Clinical Studies, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania, USA.; Department of Small Animal Clinical Sciences, University of Florida College of Veterinary Medicine.
3
Myology Institute and; Department of Physical Therapy, University of Florida, Gainesville, Florida, USA.
4
Department of Pharmacology and Therapeutics,; Myology Institute and.
5
Catabasis Pharmaceuticals, Inc., Cambridge, Massachusetts, USA.
6
Myology Institute and; Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, Florida, USA.
7
Department of Physiology and; Department of Pharmacology and Therapeutics,; Myology Institute and.

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.

Conflict of interest statement

MRJ and MZ were employees and shareholders of Catabasis Pharmaceuticals, Inc. at the time of this study. The other authors have declared that no conflict of interest exists.

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