G.P.205: A modified cysteine knot ligand trap of the TGFβ superfamily, ACE-083, increases muscle mass locally in a mouse model of Duchenne muscular dystrophy

Abstract

To investigate a new therapeutic strategy for inherited asymmetrical myopathies, we generated a modified cysteine knot ligand trap of TGFβ superfamily members, ACE-083, which acts locally to increase skeletal muscle mass. ACE-083 binds to activin and myostatin and inhibits their signaling. Unlike ActRIIB-Fc, ACE-083 does not bind to ligands BMP9/10. To demonstrate the ability of ACE-083 to increase muscle mass locally, we used a murine model of muscular dystrophy. Six week old C57BL/10ScCN-Dmd^mdx/J (mdx) and wild-type mice received intramuscular injections into the left gastrocnemius muscle of ACE-083 (100μg, 50μL, biw) or vehicle (PBS, 50μL, biw) for 4weeks. Each injection corresponded to a dose of approximately 5mg/kg. After 4weeks of treatment muscles were collected to evaluate the effect of ACE-083. In the left gastrocnemius muscle injected with 100μg ACE-083, mdx mice had increased muscle mass 16% (<i>p</i><0.01) and wild-type mice 34% (<i>p</i><0.001) compared to the non-injected, contralateral legs. Histologically, muscles injected with ACE-083 underwent hypertrophy with no signs of hyperplasia and no alteration in muscle fiber type distribution. Over the course of the study there were no significant differences in body weight between ACE-083 or vehicle treated mice. In addition, pectoral and femoris muscles were examined to determine if there was a systemic effect of locally-administered ACE-083. There was no significant increase in muscle size in the pectoral (<i>p</i>=0.838) or the femoris (<i>p</i>=0.62) muscles in either treatment group. Furthermore, we determined there was no active ACE-083 in the serum following local injections, minimizing potential off target effects in other organs. These preclinical results demonstrate that ACE-083 can effectively increase muscle mass locally following direct injection into target muscles. Therefore, local inhibition of activin and myostatin using ACE-083 represents a promising therapeutic approach for the treatment of asymmetric myopathies.