Disease-modifying effects of orally bioavailable NF-κB inhibitors in dystrophin-deficient muscle
Disease-modifying effects of orally bioavailable NF-κB inhibitors in dystrophin-deficient muscle
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DOI：
10.1172/jci.insight.90341
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发表时间：
2016-12-22
期刊：
影响因子：
8
通讯作者：
Sweeney, H. Lee
中科院分区：
文献类型：
--
作者：
Hammers, David W.;Sleeper, Margaret M.;Sweeney, H. Lee
杜氏肌营养不良症（DMD）是一种破坏性的肌肉疾病，其特征是进行性肌肉退化和替代异常脂肪，纤维基质。核因子κ B（NF-κ B）的慢性上调被认为是营养不良发病机制的驱动因素。本文中，在DMD的mdx小鼠和金毛猎犬肌营养不良（GRMD）犬模型中评价了新型NF-κ B抑制剂的2个成员edasalonexent（以前称为CAT-1004）和CAT-1041。这些口服生物可利用的化合物由与水杨酸缀合的多不饱和脂肪酸组成，并在体外有效抑制致病性NF-κ B亚基p65/RelA。在体内，CAT-1041有效地改善了mdx小鼠进行自愿轮跑的表型，包括活动、肌肉质量和功能、损伤、炎症、纤维化和心脏病理学。我们确定dysferlin的显著增加可能是CAT-1041对肌膜损伤的保护作用的贡献者。此外，CAT-1041还改善了一项犬类病例研究中更严重的GRMD表型，其中接受治疗的GRMD犬的肌肉质量和隔膜功能得到了维持。这些结果表明，通过edasalonexent和CAT-1041调节NF-κ B在改善营养不良过程中是有效的，并且这些化合物是用于DMD患者的新治疗的候选物。
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 kappa B (NF-kappa B) is implicated as a driver of the dystrophic pathogenesis. Herein, 2 members of a novel class of NF-kappa B 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-kappa B 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-kappa B modulation by edasalonexent and CAT-1041 is effective in ameliorating the dystrophic process and these compounds are candidates for new treatments for DMD patients.