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• W3148453149 abstract "In DMD, NF-kB is persistently upregulated in cardiac and skeletal muscle from infancy, driving inflammation and fibrosis, and potentially leading to myocardial fibrosis and dysfunction. Therapies to drive reverse cardiac remodelling and improve cardiac function in DMD are limited. Edasalonexent is an oral small molecule NF-kB inhibitor in Phase 3 clinical development. We hypothesized that edasalonexent could prevent cardiac dysfunction in mdx: Utrn+/- mice, a model of DMD in which cardiac dysfunction develops by 6-8 weeks of age. Edasalonexent was administered at two doses (1 and 0.3%) in the diet to mdx:Utrn+/- mice starting at 4 weeks of age. Cardiac function was assessed by echocardiography and compared to WT and mdx control mice, which do not develop early cardiomyopathy. At 16 weeks of age, cardiac tissue was collected for further analyses. Cardiac function assessed by fractional shortening was preserved in mdx:Utrn+/- mice on 1% diet after 16 weeks of edasalonexent treatment, while mice fed 0.3% or control diet developed significant reduction in cardiac function [60±3% high-dose vs 49±4% low-dose or 45±5% control diet, p<0.01; n=10-13]. Cardiac fibrosis assessed by Masson's trichrome staining was reduced in mdx:Utrn+/- hearts on high-dose edasalonexent diet compared to control diet (3.90±0.02% vs 10.50±0.03%, p=0.05, n=3-4). The ERK pathway, which enhances activating phosphorylation of NFkB/p65 at S536 and S267 positions, was downregulated by 50% in mdx:Utrn+/- hearts on high-dose edasalonexent diet compared to control diet, together with corresponding reduction in NFkB/p65 S536 and S267 phosphorylation. As expected for WT and mdx control mice, no differences in cardiac function, myocardial fibrosis, or activation of NF-kB and ERK were noted by 16 weeks of age. Collectively, the data suggest that NF-kB inhibitor edasalonexent prevents development of myocardial fibrosis and subsequent cardiac dysfunction in mdx:Utrn+/- mice." @default.
• W3148453149 created "2021-04-13" @default.
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• W3148453149 date "2020-10-01" @default.
• W3148453149 modified "2023-09-27" @default.
• W3148453149 title "DMD – ANIMAL MODELS & PRECLINICAL TREATMENT" @default.
• W3148453149 doi "https://doi.org/10.1016/j.nmd.2020.08.209" @default.
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