• First‑in‑class therapy directly targeting the dystrophic cardiac pathway • Robust in vivo efficacy across multiple DMD mouse models • Clinically tractable drug class with multiple candidate molecules provides rapid development pathways, repurposing potential: setanaxib (GKT137831), VAS2870, and GSK2795039 • Potential to combine NOX4 inhibition with dystrophin replacement therapies
Dystrophic cardiomyopathy is a leading cause of death in Duchenne muscular dystrophy (DMD) and related disorders, yet no approved therapies directly target the cardiac‑specific mechanisms driving disease. Our researchers have identified NADPH oxidase 4 (Nox4) as a causal driver of oxidative stress, fibrosis, and ventricular decline in dystrophic hearts, regulated upstream by CIP (Cardiac ISL1‑Interacting Protein), a novel regulator of cardiomyopathy.
This technology introduces a therapeutic method of using Nox4 inhibitors to prevent/ slow the progression of cardiomyopathy and heart failure in Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), X‑linked dilated cardiomyopathy (XL‑DCM), and related dystrophies. Mechanistically, NOX4 inhibition disrupts the oxidative‑stress pathway shown to drive fibrosis, ventricular dilation, and cardiomyocyte loss. Preclinical studies using severe dystrophic mouse models (including CIP‑KO/mdx and Utrn/mdx) demonstrated that daily treatment with Nox4 inhibitors significantly preserved ejection fraction, prevented left‑ventricular enlargement, and markedly reduced cardiac fibrosis. These effects were achieved using both selective and broad‑spectrum NADPH‑oxidase inhibitors, including Setanaxib (GKT137831), GKT136901, VAS2870, GSK2795039, perhexiline, APX‑115, suramin, ebselen, fulvene‑5, phenanthridinones, and several phenothiazine derivatives.
Nox4 inhibitor treatment rescues cardiac defects in mdx/CIP-/- mice: M-mode images for the control(right) and inhibitor(left) group of the 5m CIP KO/MDX mice. Quantitative EF%.