Duchenne Muscular Dystrophy (DMD) is a monogenetic disorder affecting 1 in 5000 boys. The lack of dystrophin leads to progressive muscle wasting, physical and cognitive disability and these young boys die largely due to cardio-respiratory failure. Although there are multiple efforts for cell- and gene-based therapies ongoing, currently there is no cure for DMD.
DMD is associated with the loss of neuronal nitric oxide synthase, and thus insufficient cGMP levels. We aimed to determine if an sGC stimulator, BAY41-2272, is therapeutically beneficial for DMD. We used 20wk old, male mdx/mTRG2 mice, an experimental model of DMD, and C57Bl6/J mice as wild-type (WT) controls. Mice received food containing either placebo or BAY41-2272 (300ppm) for 16wks.
Expression of the NO/sGC cascade is largely downregulated in the quadriceps of mdx/mTRG2 mice. During treatment, skeletal muscle function assessed using the rotarod, 4-limb hang and grip strength demonstrated that mdx/mTRG2 mice had impaired function, and BAY41-2272 improved grip strength. Various skeletal muscles showed minimal to marked signs of degeneration/necrosis and fibrosis in the mdx/mTRG2 mice, and BAY41-2272 improved diaphragm pathology. Contrary to a previous report, ECHO demonstrated that mdx/mTRG2 mice display normal cardiac function at 36wks. Invasive hemodynamics displayed that mdx/mTRG2 mice have reduced MAP (72.0±2.1 vs 84.1±2.1mmHg) and this was further reduced with BAY41-2272 administration (64.4±2.2mmHg).
In summary, at 36wks, mdx/mTRG2 mice have a downregulated NO/sGC system, impaired skeletal muscle function and pathology, however they display a normal cardiac phenotype compared to WT mice. BAY41-2272 treatment improved skeletal muscle function and diaphragm pathology and decreased BP of mdx/mTRG2 mice. The impact on cNMP levels are currently being assessed using mass spectrometry, and further investigations are ongoing to assess the level of muscle damage and potential treatment effects of sGC stimulators.