Follistatin-288-Fc Fusion Protein Promotes Localized Growth of Skeletal Muscle.

Autor:	Castonguay R; Acceleron Pharma, Cambridge, Massachusetts rcastonguay@acceleronpharma.com., Lachey J; Acceleron Pharma, Cambridge, Massachusetts., Wallner S; Acceleron Pharma, Cambridge, Massachusetts., Strand J; Acceleron Pharma, Cambridge, Massachusetts., Liharska K; Acceleron Pharma, Cambridge, Massachusetts., Watanabe AE; Acceleron Pharma, Cambridge, Massachusetts., Cannell M; Acceleron Pharma, Cambridge, Massachusetts., Davies MV; Acceleron Pharma, Cambridge, Massachusetts., Sako D; Acceleron Pharma, Cambridge, Massachusetts., Troy ME; Acceleron Pharma, Cambridge, Massachusetts., Krishnan L; Acceleron Pharma, Cambridge, Massachusetts., Mulivor AW; Acceleron Pharma, Cambridge, Massachusetts., Li H; Acceleron Pharma, Cambridge, Massachusetts., Keates S; Acceleron Pharma, Cambridge, Massachusetts., Alexander MJ; Acceleron Pharma, Cambridge, Massachusetts., Pearsall RS; Acceleron Pharma, Cambridge, Massachusetts., Kumar R; Acceleron Pharma, Cambridge, Massachusetts.
Jazyk:	angličtina
Zdroj:	The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2019 Mar; Vol. 368 (3), pp. 435-445. Date of Electronic Publication: 2018 Dec 18.
DOI:	10.1124/jpet.118.252304
Abstrakt:	Follistatin is an endogenous glycoprotein that promotes growth and repair of skeletal muscle by sequestering inhibitory ligands of the transforming growth factor- β superfamily and may therefore have therapeutic potential for neuromuscular diseases. Here, we sought to determine the suitability of a newly engineered follistatin fusion protein (FST288-Fc) to promote localized, rather than systemic, growth of skeletal muscle by capitalizing on the intrinsic heparin-binding ability of the follistatin-288 isoform. As determined by surface plasmon resonance and cell-based assays, FST288-Fc binds to activin A, activin B, myostatin (growth differentiation factor GDF8), and GDF11 with high affinity and neutralizes their activity in vitro. Intramuscular administration of FST288-Fc in mice induced robust, dose-dependent growth of the targeted muscle but not of surrounding or contralateral muscles, in contrast to the systemic effects of a locally administered fusion protein incorporating activin receptor type IIB (ActRIIB-Fc). Furthermore, systemic administration of FST288-Fc in mice did not alter muscle mass or body composition as determined by NMR, which again contrasts with the pronounced systemic activity of ActRIIB-Fc when administered by the same route. Subsequent analysis revealed that FST288-Fc in the circulation undergoes rapid proteolysis, thereby restricting its activity to individual muscles targeted by intramuscular administration. These results indicate that FST288-Fc can produce localized growth of skeletal muscle in a targeted manner with reduced potential for undesirable systemic effects. Thus, FST288-Fc and similar agents may be beneficial in the treatment of disorders with muscle atrophy that is focal, asymmetric, or otherwise heterogeneous. (Copyright © 2019 The Author(s).)
Databáze:	MEDLINE
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