Duchenne muscular dystrophy (DMD) presents a critical therapeutic gap in adolescent patients, where fibro-fatty muscle replacement and depletion of the regenerative niche render existing interventions insufficient. Prostaglandin E2 signaling through the EP4 receptor stimulates muscle regeneration, but systemic off-target effects have limited clinical translation of EP4 agonism. We evaluated irodanoprost (IROD), a bone-targeted prodrug of an EP4-selective agonist, in a DMD rat model using early- and late-intervention cohorts. In adolescent rats, 8 weeks of treatment reduced body weight deficit by 41.4% and restored hindlimb muscle mass and maximum tetanic force to wild-type levels. IROD dose-dependently inhibited fibro-adipogenic progenitor differentiation, facilitating resolution of established fibrosis below pre-treatment baseline, accompanied by re-activation of a regenerative program that restored the total myofiber pool to wild-type levels. A strong correlation between intramuscular fat reduction and fibrosis resolution suggests MRI-based fat imaging as a non-invasive surrogate for anti-fibrotic monitoring. Notably, while IROD selectively distributes to bone in healthy animals, markedly enhanced accumulation was observed in dystrophic muscle, establishing a pathology-targeted mechanism capable of restoring regenerative capacity in advanced DMD.
Kajabadi, N., Narasimhan, A., Chen, G., Yi, L., Rodriguez-Rodriguez, C., Coccimiglio, I. F., Huang, T., Rendeiro, M., Yamanouchi, K., Häfeli, U. O., Kostenuik, P., Young, R. N., Rossi, F.
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