ActRIIB:ALK4-Fc alleviates muscle dysfunction and comorbidities in murine models of neuromuscular disorders

Authors

Jia Li, Acceleron Pharma, Inc.
Maureen Fredericks, Acceleron Pharma, Inc.
Marishka Cannell, Acceleron Pharma, Inc.
Kathryn Wang, Acceleron Pharma, Inc.
Dianne Sako, Acceleron Pharma, Inc.
Michelle C. Maguire, Acceleron Pharma, Inc.
Rosa Grenha, Acceleron Pharma, Inc.
Katia Liharska, Acceleron Pharma, Inc.
Lavanya Krishnan, Acceleron Pharma, Inc.
Troy Bloom, Acceleron Pharma, Inc.
Elitza P. Belcheva, Acceleron Pharma, Inc.
Pedro A. Martinez, Acceleron Pharma, Inc.
Roselyne Castonguay, Acceleron Pharma, Inc.
Sarah Keates, Acceleron Pharma, Inc.
Mark J. Alexander, Acceleron Pharma, Inc.
Hyunwoo Choi, Barrow Neurological Institute
Asya V. Grinberg, Acceleron Pharma, Inc.
R. Scott Pearsall, Acceleron Pharma, Inc.
Paul Oh, Barrow Neurological Institute
Ravindra Kumar, Acceleron Pharma, Inc.
Rajasekhar N.V.S. Suragani, Acceleron Pharma, Inc.

Document Type

Article

Abstract

Patients with neuromuscular disorders suffer from a lack of treatment options for skeletal muscle weakness and disease comorbidities. Here, we introduce as a potential therapeutic agent a heterodimeric ligand-trapping fusion protein, ActRIIB:ALK4-Fc, which comprises extracellular domains of activin-like kinase 4 (ALK4) and activin receptor type IIB (ActRIIB), a naturally occurring pair of type I and II receptors belonging to the TGF-β superfamily. By surface plasmon resonance (SPR), ActRIIB:ALK4-Fc exhibited a ligand binding profile distinctly different from that of its homodimeric variant ActRIIB-Fc, sequestering ActRIIB ligands known to inhibit muscle growth but not trapping the vascular regulatory ligand bone morphogenetic protein 9 (BMP9). ActRIIB:ALK4-Fc and ActRIIB-Fc administered to mice exerted differential effects - concordant with SPR results - on vessel outgrowth in a retinal explant assay. ActRIIB:ALK4-Fc induced a systemic increase in muscle mass and function in wild-type mice and in murine models of Duchenne muscular dystrophy (DMD), amyotrophic lateral sclerosis (ALS), and disuse atrophy. Importantly, ActRIIB:ALK4-Fc improved neuromuscular junction abnormalities in murine models of DMD and presymptomatic ALS and alleviated acute muscle fibrosis in a DMD model. Furthermore, in combination therapy ActRIIB:ALK4-Fc increased the efficacy of antisense oligonucleotide M12-PMO on dystrophin expression and skeletal muscle endurance in an aged DMD model. ActRIIB:ALK4-Fc shows promise as a therapeutic agent, alone or in combination with dystrophin rescue therapy, to alleviate muscle weakness and comorbidities of neuromuscular disorders.

Publication Date

2-15-2021

Publication Title

Journal of Clinical Investigation

ISSN

00219738

E-ISSN

15588238

Volume

131

Issue

4

PubMed ID

33586684

Digital Object Identifier (DOI)

10.1172/JCI138634

Recommended Citation

Li, Jia; Fredericks, Maureen; Cannell, Marishka; Wang, Kathryn; Sako, Dianne; Maguire, Michelle C.; Grenha, Rosa; Liharska, Katia; Krishnan, Lavanya; Bloom, Troy; Belcheva, Elitza P.; Martinez, Pedro A.; Castonguay, Roselyne; Keates, Sarah; Alexander, Mark J.; Choi, Hyunwoo; Grinberg, Asya V.; Pearsall, R. Scott; Oh, Paul; Kumar, Ravindra; and Suragani, Rajasekhar N.V.S., "ActRIIB:ALK4-Fc alleviates muscle dysfunction and comorbidities in murine models of neuromuscular disorders" (2021). Translational Neuroscience. 1023.
https://scholar.barrowneuro.org/neurobiology/1023