Chronic inflammation is a hallmark of Duchenne muscular dystrophy (DMD), with glucocorticoids as the standard care to reduce inflammation, albeit with deleterious side effects. Activins and myostatin are mediators of muscle atrophy, and activins also play a crucial role in inflammation. RKER-065 is an investigational, modified type II activin receptor ligand trap designed to inhibit myostatin, activin A, and activin B. This study compares the treatment effect of RKER-065 with glucocorticoids in a DMD mouse model and evaluates its anti-inflammatory effects against the standard of care in alleviating DMD pathology.
Six-week-old male D2.MDX mice were treated for 9 weeks with vehicle (PBS, i.p. OD, and TBS, i.p. BIW), prednisolone (Pred, 4mg/m2 i.p., QD and TBS, i.p. BIW), or RKER-065 (PBS, i.p. OD, RKER-065 10mg/kg, i.p., BIW). Vehicle-treated DBA2/J served as controls (WT). Mice were assessed for lean mass, grip strength, and expression of inflammatory markers and dystrophin in muscle.
Vehicle-treated D2.MDX mice exhibited reduced lean mass gain, grip strength, and increased expression of inflammatory markers (i.e., CD68, CD40, IL-1b, and TNFR1α) in muscle, compared to WT mice. Treatment with Pred further reduced lean mass gain and failed to improve grip strength. RKER-065 treatment increased lean mass gain and grip strength in D2.MDX mice, comparable to the WT group, outperforming vehicle and Pred groups. Chronic treatment with Pred suppressed the expression of CD68 but not CD40, IL-1b or TNFR1α. In contrast, RKER-065 significantly reduced the expression of CD40, IL-1b, TNFR1α, CD11b, and CD68. Moreover, RKER-065-treated mice showed higher dystrophin protein and mRNA levels relative to both vehicle and Pred groups.
These findings suggest that RKER-065 preserved muscle, increased dystrophin level, and provided better anti-inflammation benefits compared to prednisolone in the DMD mouse model, highlighting its potential as a steroid-sparing treatment for DMD.