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 <i>mdx</i> 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 <i>mdx</i> 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.