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

Scientific Reports
R Scott PearsallRavi Kumar

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 p...Continue Reading

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Citations

Nov 24, 2019·Drug Testing and Analysis·Christian ReichelMario Thevis
Aug 11, 2020·Current Opinion in Neurology·Kathryn R Wagner
Jul 24, 2020·Expert Opinion on Therapeutic Targets·Alexander RiesMichael Grusch
Sep 11, 2020·Journal of Bone Metabolism·Joonho Suh, Yun-Sil Lee
Oct 24, 2020·Trends in Molecular Medicine·Justin CohenAngela Lek
Feb 14, 2021·Journal of Neuromuscular Diseases·Leo H Wang, Rabi Tawil
Feb 16, 2021·The Journal of Clinical Investigation·Jia LiRajasekhar Nvs Suragani
May 3, 2021·Cytokine & Growth Factor Reviews·Andreas Lodberg
May 4, 2021·The Journal of Clinical Investigation·Se-Jin Lee
Jul 3, 2021·International Journal of Molecular Sciences·Pierre Miniou, Michel Fontes
Sep 17, 2021·Scientific Reports·Ravindra KumarRoselyne Castonguay
Sep 15, 2021·Endocrine Reviews·Buel D Rodgers, Christopher W Ward

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Methods Mentioned

BETA
surface
biosensor
surface plasmon resonance
PCR
Assay

Software Mentioned

GraphPad Prism
GraphPad
BIAevaluation

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