Smad7 gene delivery prevents muscle wasting associated with cancer cachexia in mice

• Published in: Science translational medicine 2016-07, Vol.8 (348), p.348ra98-348ra98
• Main Authors: Winbanks, Catherine E, Murphy, Kate T, Bernardo, Bianca C, Qian, Hongwei, Liu, Yingying, Sepulveda, Patricio V, Beyer, Claudia, Hagg, Adam, Thomson, Rachel E, Chen, Justin L, Walton, Kelly L, Loveland, Kate L, McMullen, Julie R, Rodgers, Buel D, Harrison, Craig A, Lynch, Gordon S, Gregorevic, Paul
• Format: Article
• Language: English
• Subjects: Activin Receptors, Type II - genetics; Activin Receptors, Type II - metabolism; Animals; Blotting, Western; Mice; Muscle Proteins - genetics; Muscle Proteins - metabolism; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscular Atrophy - etiology; Muscular Atrophy - metabolism; Muscular Atrophy - therapy; Myocardium - metabolism; Myocardium - pathology; Neoplasms - complications; Neoplasms - metabolism; Neoplasms - physiopathology; Phosphorylation - genetics; Phosphorylation - physiology; Signal Transduction - genetics; Signal Transduction - physiology; SKP Cullin F-Box Protein Ligases - genetics; SKP Cullin F-Box Protein Ligases - metabolism; Smad2 Protein - genetics; Smad2 Protein - metabolism; Smad3 Protein - genetics; Smad3 Protein - metabolism; Smad7 Protein - genetics; Smad7 Protein - metabolism; Tripartite Motif Proteins - genetics; Tripartite Motif Proteins - metabolism; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism
• ISSN: 1946-6234; 1946-6242
• DOI: 10.1126/scitranslmed.aac4976

Patients with advanced cancer often succumb to complications arising from striated muscle wasting associated with cachexia. Excessive activation of the type IIB activin receptor (ActRIIB) is considered an important mechanism underlying this wasting, where circulating procachectic factors bind ActRIIB and ultimately lead to the phosphorylation of SMAD2/3. Therapeutics that antagonize the binding of ActRIIB ligands are in clinical development, but concerns exist about achieving efficacy without off-target effects. To protect striated muscle from harmful ActRIIB signaling, and to reduce the risk of off-target effects, we developed an intervention using recombinant adeno-associated viral vectors (rAAV vectors) that increase expression of Smad7 in skeletal and cardiac muscles. SMAD7 acts as an intracellular negative regulator that prevents SMAD2/3 activation and promotes degradation of ActRIIB complexes. In mouse models of cachexia, rAAV:Smad7 prevented wasting of skeletal muscles and the heart independent of tumor burden and serum levels of procachectic ligands. Mechanistically, rAAV:Smad7 administration abolished SMAD2/3 signaling downstream of ActRIIB and inhibited expression of the atrophy-related ubiquitin ligases MuRF1 and MAFbx. These findings identify muscle-directed Smad7 gene delivery as a potential approach for preventing muscle wasting under conditions where excessive ActRIIB signaling occurs, such as cancer cachexia.