Inhibition of NF-kB signaling by edasalonexent prevents the development of DMD-associated cardiomyopathy in mdx : Utrn+/- mice


Early Stage Drug Development Partnerships

Poster Number: 74


Pradeep Mammen, MD, Jian Huang, PhD, Terry Gemelli, BS, Pradeep Bista, PhD, Tara Tassin, PhD, Xuan Jiang, PhD, John Shelton, BS, Andrew Nichols, PhD, Joanne Donovan, MD, PhD


1. UT Southwestern Medical Center, 2. UT Southwestern Medical Center, 3. UT Southwestern Medical Center, 4. Catabasis Pharmaceuticals, 5. UT Southwestern Medical Center, 6. UT Southwestern Medical Center, 7. UT Southwestern Medical Center, 8. Catabasis Pharmaceuticals, 9. Catabasis Pharmaceuticals

Background and Hypothesis: In Duchenne muscular dystrophy (DMD), NF-κB signaling is upregulated in cardiac and skeletal muscle from infancy and drives inflammation and fibrosis. Therapies to drive reverse cardiac remodeling and improve overall cardiac function in DMD are limited. Edasalonexent is an oral small molecule NF-kB inhibitor that is currently in the Phase 3 PolarisDMD trial for young boys with DMD. We hypothesized that NF-kB inhibition by edasalonexent could prevent cardiac dysfunction in DMD(mdx:Utrn+/-) mice, a model of DMD in which significant cardiac dysfunction develops by 6-8 weeks of age.

Methods: Edasalonexent was administered at two doses (1 and 0.3%) in diet to DMD(mdx:Utrn+/-) mice starting at 4 weeks of age. Cardiac function was assessed by echocardiography and compared to WT and DMD(mdx) control mice which do not develop early cardiomyopathy. At 16 weeks of age, cardiac tissue was collected for histological and molecular analyses.

Results: Food consumption was similar in all groups. Overall cardiac function as assessed by fractional shortening was preserved in DMD(mdx:Utrn+/-) mice on 1% edasalonexent diet after 12 weeks of treatment, while mice fed 0.3% edasalonexent diet or control diet developed significant reduction in cardiac function [fractional shortening: 60±3% high-dose vs 49±4% low-dose or 45±5% control diet, p<0.01; n=4-6]. Cardiac fibrosis assessed by Masson’s trichrome staining was reduced in DMD(mdx:Utrn+/-) hearts on high-dose edasalonexent diet compared to the control diet (4.94±0.01% vs 11.67±0.03%, p=0.05, n=3). As expected, no difference in cardiac function or myocardial fibrosis was noted in either WT or DMD(mdx) control mice by 16 weeks of age.

Conclusions: These data suggest that the NF-kB inhibitor edasalonexent prevents development of myocardial fibrosis and subsequent cardiac dysfunction in DMD(mdx:Utrn+/-) mice. Further studies are ongoing to determine the precise molecular mechanism underlying this observation.