2. Academic Validation
  3. Disease-modifying effects of orally bioavailable NF- κ B inhibitors in dystrophin-deficient muscle

Disease-modifying effects of orally bioavailable NF- κ B inhibitors in dystrophin-deficient muscle

  • JCI Insight. 2016 Dec 22;1(21):e90341. doi: 10.1172/jci.insight.90341.
David W Hammers 1 2 3 4,  Margaret M Sleeper 4 5 6,  Sean C Forbes 4 7,  Cora C Coker 3 4,  Michael R Jirousek 8,  Michael Zimmer 8,  Glenn A Walter 4 9,  H Lee Sweeney 1 3 4
Affiliations

Affiliations

  • 1 Department of Physiology and.
  • 2 Pennsylvania Muscle Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
  • 3 Department of Pharmacology and Therapeutics.
  • 4 Myology Institute and.
  • 5 Department of Clinical Studies, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania, USA.
  • 6 Department of Small Animal Clinical Sciences, University of Florida College of Veterinary Medicine.
  • 7 Department of Physical Therapy, University of Florida, Gainesville, Florida, USA.
  • 8 Catabasis Pharmaceuticals, Inc., Cambridge, Massachusetts, USA.
  • 9 Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, Florida, USA.
PMID: 28018975 DOI: 10.1172/jci.insight.90341
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.

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