Résumé :
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Activin receptor type IIB (ActRIIB) is a signaling receptor for ligands involved in suppressing muscle growth. Blocking ActRIIB signaling increases muscle mass and function. RAP-031, a soluble fusion protein comprised of a form of ActRIIB extracellular domain fused to a murine Fc, also increases muscle mass and improves muscle weakness in mdx mice. There is currently no cure for Duchenne muscular dystrophy (DMD); however, glucocorticoids, such as prednisolone, slow disease progression and are commonly used for the management of disease. To study the effect of combined glucocorticoid/RAP-031 regime in a dystrophy model, mdx mice received either: vehicle/vehicle (VEH/VEH), prednisolone /vehicle (PRED/VEH) or prednisolone/RAP-031 (PRED/RAP). Prednisolone was dosed 5 mg/kg, 5X/week, po and RAP-031 was dosed once weekly at 10 mg/kg sc. At 2 weeks, PRED/VEH gained 8.5% less body weight (p<0.01) than VEH/VEH. In contrast, PRED/RAP gained body weight at a similar rate to VEH/VEH. NMR analysis established the body weight effect was due to decreased lean mass gain in PRED/VEH (p<0.01) compared to VEH/VEH whereas PRED/RAP gained lean mass similarly to VEH/VEH. At study day 9, VEH/VEH and PRED/VEH had comparable absolute forelimb grip strength, but given the PRED/VEH cohort had reduced lean mass, their grip strength per unit of muscle is greater (p<0.05). PRED/RAP mice had significantly greater absolute grip strength (p<0.05 compared to VEH/VEH and PRED/VEH). Importantly, the normalized grip strength improvement is retained in PRED/RAP (VEH/VEH=p<0.05, PRED/VEH=ns). Therefore, RAP-031 improved mdx muscle function in mice by increasing overall lean mass or by preventing lean mass loss, as is the case when given with prednisolone. In contrast, prednisolone improved muscle function independent from a lean mass increase. These data support the use of ACE-031, the human version of RAP-031, as a potential distinct therapeutic for the treatment of DMD.
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