2. Academic Validation
  3. Follistatin-based ligand trap ACE-083 induces localized hypertrophy of skeletal muscle with functional improvement in models of neuromuscular disease

Follistatin-based ligand trap ACE-083 induces localized hypertrophy of skeletal muscle with functional improvement in models of neuromuscular disease

  • Sci Rep. 2019 Aug 6;9(1):11392. doi: 10.1038/s41598-019-47818-w.
R S Pearsall 1,  M V Davies 2,  M Cannell 2,  J Li 2,  J Widrick 3,  A W Mulivor 2 4,  S Wallner 2 5,  M E Troy 2,  M Spaits 2,  K Liharska 2 6,  D Sako 2,  R Castonguay 2,  S Keates 2,  A V Grinberg 2 6,  R N V S Suragani 2,  R Kumar 2
Affiliations

Affiliations

  • 1 Acceleron Pharma, Cambridge, MA, USA. [email protected].
  • 2 Acceleron Pharma, Cambridge, MA, USA.
  • 3 Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • 4 The Hospital for Sick Children, Toronto, Ontario, Canada.
  • 5 NovaRock Biotherapeutics, Princeton, NJ, USA.
  • 6 Dragonfly Therapeutics, Waltham, MA, USA.
PMID: 31388039 DOI: 10.1038/s41598-019-47818-w
Abstract

Skeletal muscle is under inhibitory homeostatic regulation by multiple ligands of the Transforming Growth Factor-β (TGFβ) superfamily. Follistatin is a secreted protein that promotes muscle growth and function by sequestering these ligands extracellularly. In the present study, we evaluated the potential of ACE-083 - a locally acting, follistatin-based fusion protein - as a novel therapeutic agent for focal or asymmetric myopathies. Characterization of ACE-083 in vitro revealed its high affinity for heparin and extracellular matrix while surface plasmon resonance and cell-based assays confirmed that ACE-083 binds and potently neutralizes myostatin, Activin A, Activin B and Growth Differentiation Factor 11 (GDF11). Intramuscular administration of ACE-083 caused localized, dose-dependent hypertrophy of the injected muscle in wild-type mice and mouse models of Charcot-Marie-Tooth disease (CMT) and Duchenne muscular dystrophy, with no evidence of systemic muscle effects or endocrine perturbation. Importantly, ACE-083 also increased the force of isometric contraction in situ by the injected tibialis anterior muscle in wild-type mice and disease models and increased ankle dorsiflexion torque in CMT mice. Our results demonstrate the potential of ACE-083 as a therapeutic agent for patients with CMT, muscular dystrophy and other disorders with focal or asymmetric muscle atrophy or weakness.

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