Background: Corticosteroids are a cornerstone in the treatment of Duchenne Muscular Dystrophy (DMD). However, their long-term use causes a multitude of adverse effects, which pose a heavy burden on patients. New therapeutic options that minimize steroid usage are highly desirable.
MP1032 is a small-molecule drug candidate that like corticosteroids elicits anti-inflammatory effects. However, MP1032 acts via modulating and stabilizing macrophage and mitochondrial function, a mechanism of action that is distinctly different from steroidal drugs. In previous non-DMD pre-clinical and clinical studies, MP1032 has demonstrated an outstanding safety profile, lacking any of the known steroid-associated side effects.
Objectives: To compare the effects of MP1032, prednisolone and deflazacort on inflammation and muscle strength in the mdx mouse model.
Methods: 5-week-old mdx mice (C57BL/10ScSn-Dmdmdx/J) were treated daily with either vehicle, MP1032, prednisolone or deflazacort over a 5-week period. Muscle strength of the extensor digitorum longus (EDL) was assessed in an ex vivo muscle-force assay at the end of treatment. Inflammation in skeletal muscle was assessed by quantification of inflammatory foci in whole mount sections from tibialis anterior (TA) muscle and by quantitative RT-PCR of pro-inflammatory cytokines.
Results: MP1032 showed similar efficacy in improving EDL muscle strength compared to prednisolone and was superior to deflazacort. Overall inflammation in the TA muscle was markedly reduced by MP1032, but not by steroid treatment. An even more pronounced anti-inflammatory effect in muscle was seen when comparing the downregulation of pro-inflammatory cytokines IL-1ß, IL-6 and TNF-α between MP1032 versus steroid treated animals. Furthermore, in a human cell co-culture system, MP1032 plus low-dose corticosteroids showed highly supra-additive efficacy in down-modulating pro-inflammatory cytokines.
Conclusion: MP1032 holds potential to substantially reduce steroid doses in the management of DMD while maintaining or even improving therapeutic outcomes. Also, this could substantially mitigate the detrimental steroid-associated side effects in DMD patients.