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

R S Pearsall,S Keates,M Cannell,J Widrick,S Wallner,R N V S Suragani,R Castonguay,J Li,A V Grinberg,R Kumar,K Liharska,M E Troy,D Sako,M V Davies,A W Mulivor,M Spaits

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.

Highlights

Weakness or loss of skeletal muscle can arise from multiple causes, including hereditary neuromuscular disorders, acquired diseases, sarcopenia, trauma, athletic injuries and disuse
ACE-083 is a novel, dimeric fusion protein in which human FST291 is coupled to the Fc domain of human IgG2 (Fig. 1a) to obtain pharmacokinetic properties similar to those of an antibody[27]
We evaluated the ability of ACE-083 to induce focal muscle hypertrophy in the Trembler-J mouse model of CMT1A35, which harbors a mutation in peripheral myelin protein 22 (Pmp22), a gene critical in the etiology of CMT1A

Summary

Introduction

Weakness or loss of skeletal muscle can arise from multiple causes, including hereditary neuromuscular disorders, acquired diseases, sarcopenia, trauma, athletic injuries and disuse. Therapeutic interventions based on these follistatin isoforms, or derivatives thereof, have demonstrated efficacy in normal animals and disease models through improvements in muscle mass, strength, regeneration and fibrosis[16,17,18,19,20,21,22]. These studies provide a compelling rationale for follistatin-based therapies as systemically acting inducers of muscle growth but do not address the potential of such agents for focused local therapy. The objective of the present study was to evaluate ACE-083 – a novel, FST291-Fc fusion protein currently in clinical development24–26 – for its ability to produce focal muscle hypertrophy and increased strength in normal mice and murine models of neuromuscular disease

Objectives

Methods

Results

Conclusion