RNA-seq analysis to assess preclinical cardiac benefits of acute resolution pharmacology therapy for Duchenne Muscular Dystrophy (DMD)
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Duchenne Muscular Dystrophy (DMD) is a progressive X-linked disorder caused by mutations in the DMD gene, leading to the loss of dystrophin and subsequent skeletal and cardiac muscle degeneration. Cardiac complications, particularly dilated cardiomyopathy, are a major cause of early mortality in DMD. In the heart, dystrophin deficiency triggers immune dysregulation, chronic inflammation, and extracellular matrix (ECM) remodeling, culminating in fibrotic damage and heart failure.This RNA-seq study evaluates the mechanism for cardiac benefit of BMS-986235, a selective FPR2 agonist, in the D2-mdx mouse model of DMD. It reveals significant dystrophin deficit leads to upregulation of immune and fibrotic genes, including Il1b, Cd68, Fn1, and Spp1 in D2-mdx heart, which are downregulated by acute treatment with BMS-986235. Additionally, this treatment also caused the expression of genes associated with resolution of inflammation and with tissue repair to be elevated. These findings suggest that FPR2 activation via BMS-986235 fosters a reparative immune environment, selectively modulating immune-fibrotic interactions without broad immunosuppression. This preclinical study provides insights into the potential mechanism by which BMS-986235 can function as a disease-modifying therapy for DMD cardiomyopathy, warranting further functional and translational evaluation.
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