Niche-reprogramming CAR T therapy improves skeletal muscle regeneration and function in preclinical murine models of Duchenne muscular dystrophy

Abstract

Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disorder with no cure. Emerging dystrophin-restoring gene therapies target mutant myofibers but face challenges in efficacy and toxicities, underscoring the need for new treatments. Current therapies do not address chronic inflammation and muscle fibrosis, key pathologies creating a pathological muscle microenvironment that impairs dystrophic muscle function and regeneration. Here, we identify urokinase plasminogen activator receptor (uPAR) as a shared surface marker on subsets of macrophages and fibro-adipogenic progenitors exhibiting strong pro-inflammatory and fibrogenic signatures in DMD. Notably, uPAR-directed chimeric antigen receptor (CAR) T cells selectively eliminate these pathogenic subpopulations, remodel the muscle microenvironment, and enhance dystrophic muscle regeneration and force production; they also improve diaphragm and respiratory function, addressing an unmet clinical need and a major cause of DMD mortality. These findings establish uPAR CAR T cells as a niche-remodeling regenerative immunotherapy that simultaneously addresses multiple DMD pathologies and improves dystrophic muscle regeneration and function.