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

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.

Activin A: an emerging target for improving cancer treatment?

“…Blocking activin A can also be performed by using its physiological binding proteins follistatin or fstl-3/FLRG or derivatives thereof. Fusing follistatin to the Fc domain of human IgG2 (ACE-083) [120] and a gene therapy approach expressing follistatin from an adeno-associated virus (AAV) vector [121] have been tested as potential therapeutics for muscle diseases but not in cancer patients. Follistatin was shown to decrease radiation-induced fibrosis in a mouse model [122], an observation of potential interest for cancer radiotherapy.…”

Detection of follistatin‐based inhibitors of the TGF‐β signaling pathways in serum/plasma by means of LC‐HRMS/MS and Western blotting

“…Follistatin (FST) is a monomeric secretory glycoprotein, which is expressed in nearly all tissues and functions as extracellular ligand trap regulating the bioavailability of different transforming growth factor beta (TGF‐β) cytokines such as myostatin and activin A 1,2 . Whereas myostatin is considered as key regulator of muscle growth, activin A controls the synthesis and secretion of the follicle‐stimulating hormone (FSH) as well as myogenesis 3–5 .…”

Detection of black market follistatin 344

“…8 Due to its potential performance enhancing properties, follistatin is prohibited according to the WADA list 2019 (chapter S4 "Hormone and metabolic modulators"). 9 So far, most follistatin administration studies have been performed in mouse models only 8,[10][11][12][13][14] and currently, there is no approved follistatin pharmaceutical available. However, follistatin is accessible on the black market.…”

“…Five antibodies performed with very low (ab157471, ab64490, ab58920; lanes 2-4) to low recoveries (SAB2100858, SAB1402515; lanes[8][9]. Of the remaining seven antibodies, only three (NBP1-79163, BAF669, ab47942; lanes[11][12][13] showed no cross-reactions with other proteins present (i.e. remaining BSA from Dynabeads, light and heavy chains of antibodies after heating in LDS sample buffer).…”