A study investigating the use of a new soluble guanylyl cyclase (sGC) stimulator, BAY-747, for the treatment of Duchenne muscular dystrophy (DMD), found that it “improved skeletal muscle function, reduced serum creatine kinase levels, and biomarkers of inflammation and fibrosis in the skeletal muscle with no effect on myeloid cell infiltration and collagen accumulation.”
The preclinical study was published in the International Journal of Molecular Sciences.
While the therapy did have an effect on these factors in the murine model of DMD, the authors noted that the treatment effects were only moderate and that dose escalation may not be possible due to BAY-747’s dose-dependent blood pressure reduction effect. The authors stated, “sGC stimulators [like BAY-747] might provide an adjunctive treatment modality for DMD patients rather than a stand-alone option, similar to current treatment regimens which include combinations like MR-antagonists with ACE-inhibitors.”
Read more about DMD therapies
BAY-747 (N-(2-amino-2-methylbutyl)-8-[(2,6-difluorobenzyl)oxy]-2,6-dimethylimidazo [1,2-a]pyridine-3-carboxamide) works through activation of the sGC enzyme to increase levels of cyclic guanosine monophosphate (cGMP) in skeletal muscles. Previously, cGMP has been shown to increase vasodilatation and perfusion in skeletal muscles, improving oxygen delivery and exercise efficiency.
The present study found that BAY-747 was able to increase cGMP levels in some but not all skeletal muscles of a mouse model of DMD (mdx/mTRG2 mice). Treatment with BAY-747 also improved grip strength and running wheel speed in this mouse model.
While the treated mice showed increased speed on the running wheel, they did not increase their overall distance run. The treated mice also had decreased serum creatine kinase levels compared to untreated mice but there were no improvements in skeletal muscle pathology.
Further results showed that BAY-747 reduced the expression of some inflammatory biomarkers including tumor necrosis factor (TNF), interleukin-6 (IL-6), and chemokine CCL2 but failed to reduce the infiltration of immune cells into the skeletal muscles of treated mice. Similarly, treatment with BAY-747 showed reduced activity of genes in the transforming growth factor β (TGFβ)-dependent pathway but this did not result in decreased levels of collagen accumulation within muscle cells.
Krishnan SM, Nordlohne J, Dietz L, et al. Assessing the use of the sGC stimulator BAY-747, as a potential treatment for Duchenne muscular dystrophy. Int J Mol Sci. 2021;22(15):8016. doi:10.3390/ijms22158016