Duchenne muscular dystrophy (DMD) is a lethal, progressive neuromuscular disorder inherited as an X-linked disease caused by mutations in the dystrophin gene, leading to progressive muscle degeneration and wasting. Beyond the structural role of dystrophin loss, increasing evidence indicates that dystrophin deficiency triggers additional pathogenic mechanisms contributing to muscle cell necrosis, including dysregulation of Store-Operated Calcium Entry (SOCE).
SOCE is a fundamental Ca²⁺ homeostatic mechanism activated by depletion of intracellular Ca²⁺ stores, resulting in Ca²⁺ influx through plasma membrane channels. This process is primarily mediated by the endoplasmic reticulum Ca²⁺ sensor STIM and the plasma membrane Ca²⁺ channel ORAI.
In this study, we characterized SOCE dysregulation in both ex vivo and in vivo models of DMD and evaluated the therapeutic potential of CIC-39, a negative modulator of SOCE. Calcium imaging analyses demonstrated that SOCE is significantly overactivated in peripheral blood mononuclear cells (PBMCs) and myotubes derived from DMD patients, independently of the specific dystrophin gene mutation. Importantly, CIC-39 effectively counteracted this overactivation, restoring intracellular Ca²⁺ levels to physiological values and significantly reducing inflammation and fibrosis in patient-derived PBMCs and myotubes.
Consistently, SOCE overactivation was also observed in mdx-derived myotubes. In vivo treatment with CIC-39 in mdx mice led to reduced plasma creatine kinase levels, attenuation of muscle damage and apoptosis, and a marked decrease in muscle inflammation and fibrosis.
Taken together, these findings indicate that SOCE overactivation represents a mutation-independent pathogenic mechanism in DMD. The demonstrated efficacy of CIC-39 in ex vivo and in vivo models supports SOCE as a druggable target and identifies CIC-39 as a promising therapeutic strategy to attenuate disease progression and ameliorate clinical manifestations of DMD.