A. Nichols, J. Reilly, F. Liu
Oct 1, 2017
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Neuromuscular Disorders
Abstract
and promotes muscle degeneration while inhibiting muscle regeneration. NF-kB driven micro-RNA also directly impair dystrophin protein translation, further destabilizing this protein and limiting the full potential of exon-skipping therapy in dystrophic muscles. Edasalonexent is an oral NF-kB inhibitor that is currently in the MoveDMD® trial in DMD boys aged 4-7, an age range where high burden of inflammation in the muscle is expected. Previously, edasalonexent has been shown to inhibit muscle inflammation and fibrosis, and to improve muscle function and exercise endurance in mdx mice and GRMD dogs. Here, we show that in primary human skeletal muscle myoblasts derived from multiple donors, treatment with edasalonexent enhances their differentiation into myotubes. In an in vitro pro-inflammatory context, simulated by the addition of IL-1β and TNFα, myotube formation was suppressed, and treatment with edasalonexent partially rescued myotube formation. In young mdx mice where muscle inflammation is prominent, edasalonexent treatment reduced inflammatory infiltration in the skeletal muscle while enhancing sarcolemmal integrity. In combination with an exon-skipping agent, edasalonexent treatment further enhanced the sarcolemmal dystrophin detected in the quadriceps of mdx mice beyond that produced by exon skipping alone. The increase in dystrophin levels with edasalonexent combination treatment extended to the heart, a tissue known to have low efficiency of dystrophin upregulation by these agents when used alone. These results demonstrate that inhibition of NF-kB by edasalonexent in a pro-inflammatory environment enhances myotube formation in vitro. Furthermore, edasalonexent treatment of dystrophic mdx mice enhances muscle fiber integrity, and in combination with an exon-skipping agent, enhances sarcolemmal dystrophin expression. Abstract Edasalonexent (CAT-1004), an NF-kB inhibitor, enhances myotube formation in vitro, and increases exon-skipped sarcolemmal dystrophin in muscle of mdx mice Nichols, A.1, Reilly, J. 1, Liu, F. 1, Bista, P. 1, Lee, D. 1, Webb, S. 1, Picarella, D. 1, Wood, J. 2, Yao, M. 2, Passini, M. 2, Estrella, N. 2 1 Catabasis Pharmaceuticals, Inc. Cambridge USA , 2Sarepta Therapeutics, Inc. Cambridge USA