Assessing the Use of the sGC Stimulator BAY-747, as a Potential Treatment for Duchenne Muscular Dystrophy.

Shalini Murali Krishnan,Alexandros Vakalopoulos,Jörg Hüser,Petra Haning,Johannes Nordlohne,Roland Seifert,Peter Sandner,Lisa Dietz,Ilka Mathar,Elke Hartmann

doi:10.3390/ijms22158016

Abstract

Duchenne muscular dystrophy (DMD) is a severe and progressive muscle wasting disorder, affecting one in 3500 to 5000 boys worldwide. The NO-sGC-cGMP pathway plays an important role in skeletal muscle function, primarily by improving blood flow and oxygen supply to the muscles during exercise. In fact, PDE5 inhibitors have previously been investigated as a potential therapy for DMD, however, a large-scale Phase III clinical trial did not meet its primary endpoint. Since the efficacy of PDE5i is dependent on sufficient endogenous NO production, which might be impaired in DMD, we investigated if NO-independent sGC stimulators, could have therapeutic benefits in a mouse model of DMD. Male mdx/mTRG2 mice aged six weeks were given food supplemented with the sGC stimulator, BAY-747 (150 mg/kg of food) or food alone (untreated) ad libitum for 16 weeks. Untreated C57BL6/J mice were used as wild type (WT) controls. Assessments of the four-limb hang, grip strength, running wheel and serum creatine kinase (CK) levels showed that mdx/mTRG2 mice had significantly reduced skeletal muscle function and severe muscle damage compared to WT mice. Treatment with BAY-747 improved grip strength and running speed, and these mice also had reduced CK levels compared to untreated mdx/mTRG2 mice. We also observed increased inflammation and fibrosis in the skeletal muscle of mdx/mTRG2 mice compared to WT. While gene expression of pro-inflammatory cytokines and some pro-fibrotic markers in the skeletal muscle was reduced following BAY-747 treatment, there was no reduction in infiltration of myeloid immune cells nor collagen deposition. In conclusion, treatment with BAY-747 significantly improves several functional and pathological parameters of the skeletal muscle in mdx/mTRG2 mice. However, the effect size was moderate and therefore, more studies are needed to fully understand the potential treatment benefit of sGC stimulators in DMD.

Highlights

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder caused by mutations in the gene encoding the dystrophin protein
Downstream target PRKG2 were downregulated in the quadriceps of 22-week-old adult mdx/mTRG2 mice compared to age-matched wild type mice (Figure 1)
Similar to pro-inflammatory markers, mRNA expression of markers of fibrosis including that of various collagen subtypes (COL1A1, COL1A2, COL3A1), matrix metalloproteinase 2 (MMP2), tissue inhibitor of matrix metalloproteinase 1 (TIMP1), fibronectin, transforming growth factor β (TGFβ) and connective tissue growth factor (CTGF) were all significantly increased in the quadriceps muscle of 22-week old mdx/mTRG2 mice compared to age-matched wild type mice (Figure 7A–H)

Summary

Introduction

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder caused by mutations in the gene encoding the dystrophin protein. The lack of a fully functional dystrophin protein results in severe and progressive weakness of both the skeletal and cardiac muscles. It is considered a rare disease, DMD is the most common form of muscular dystrophy affecting one in 3500 to 5000 boys worldwide [1] with these boys generally diagnosed between the age of 3 to 5 years. In young adults affected with DMD, muscle dysfunction starts to affect cardiac and respiratory function, eventually requiring artificial ventilation to aid respiration. In order to improve the quality and longevity of life, currently a comprehensive multi-disciplinary approach is used to manage DMD, involving pharmacological and nonpharmacological therapies that mostly improve symptoms, along with regular assessments of orthopedics, cardiology, pulmonology, osteology as well as mental health [2,3,4]

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Results

Conclusion