ADAMTS-5 inhibition reduces muscle inflammation and fibrosis and improves function in mouse models of Duchenne muscular dystrophy

In muscles of patients with Duchenne muscular dystrophy (DMD), expression of extracellular matrix proteases and proteoglycans, including A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS-5) and its substrates versican and fibronectin, is increased. Elevated ADAMTS-5 protease activity results in proinflammatory matrikines, including versikine. Here, we hypothesized that targeting ADAMTS-5 with the small-molecule inhibitor GLPG1972 could decrease dystrophic pathology. Using versikine as a marker of target engagement, we observed a robust reduction in human serum after up to 52 weeks of treatment with GLPG1972, confirming inhibition of ADAMTS-5 catalytic activity. Treatment of C57.muscular dystrophy x-linked ( mdx ) mice with GLPG1972, alone or in combination with the standard-of-care prednisolone, increased forelimb grip strength and force output of diaphragm muscles ex vivo when compared with vehicle treatment, and improvements in function were associated with decreased diaphragm inflammation and fibrosis. Treatment of C57. mdx mice with prednisolone also decreased diaphragm inflammation; however, grip strength, diaphragm force output, and fibrosis did not significantly differ from vehicle treatment. In D2. mdx mice, GLPG1972 improved forelimb grip strength and wire hang time compared with vehicle. Furthermore, GLPG1972 increased the strength of fast tibialis anterior muscles in situ and slow soleus muscles ex vivo, and this was associated with decreased inflammation, sarcolemma damage, and fibronectin deposition as assessed by immunohistochemistry. Together, these findings position ADAMTS-5 inhibition with GLPG1972 for further study as a disease-modifying strategy for DMD that may achieve both anti-inflammatory and antifibrotic effects on muscle, resulting in improved contractile function.