Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disorder that results in progressive myofiber loss. Patients develop muscle weakness, cardiac arrhythmias, and respiratory weakness. The nuclear export protein XPO1/CRM1 is a promising target for treatment of neuromuscular disorders with inflammatory muscle pathologies, such as DMD. XPO1 regulates the subcellular localization of >200 cargo proteins, including transcription factors that control inflammation and neurotoxicity. SINE compounds are orally available small molecules that inhibit XPO1 nuclear export function. Treatment with SINE compounds have improved phenotypes in other neuromuscular disease models, including ALS and Huntington’s, via reducing fibrosis, neurotoxicity, and inflammation in skeletal muscle.
To ascertain the effect of SINE compounds on dystrophic disease pathologies, sapje (DMD mutant) zebrafish embryos were treated short-term (5 days) or long-term (3 weeks) with either vehicle, SINE compound, or aminophylline (positive control). In both experiments, the SINE compound-treated sapje zebrafish showed significant reduction in muscular degeneration as well as improved muscle architecture. Moreover, a significant lifespan extension of treated-fish was observed. Next, we tested SINE compound in adult mdx (DBA2J) and WT mice 3x/week for 8 weeks. Consistent with previous results, SINE compound treatment in mdx mice improved mobility and muscle integrity. Additionally, inflammation was decreased due a reduction of inflammatory cytokines and an increase in pro-regenerative M2-macrophages. RNA-sequencing analyses of SINE-treated muscles demonstrated differential regulation of critical genes involved in DMD pathology. Interestingly, a couple of our top affected genes are circadian clock genes, which warrants further investigation. Our studies demonstrate that SINE compounds are a promising therapeutic that attenuates the symptoms in relevant animal models of DMD.