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

See allHide authors and affiliations

Science Translational Medicine  20 Jul 2016:
Vol. 8, Issue 348, pp. 348ra98
DOI: 10.1126/scitranslmed.aac4976

You are currently viewing the abstract.

View Full Text

Taking action against cachexia

An unfortunate morbidity associated with cancer is muscle wasting, known as cachexia, where healthy cells erode in the face of malignancy. Cachexia has been difficult to treat, and the most promising new therapies inhibiting ActRIIB ligands, such as myostatin, a protein that promotes muscle breakdown, have been pulled after clinical trials indicated safety issues. Targeting ActRIIB ligands may still be possible—just in a different way, to avoid toxicity. Winbanks et al. demonstrated that gene therapy could be used to block ActRIIB ligands’ catabolic signaling. Delivering the gene Smad7 to mice with tumors prevented muscle atrophy and preserved muscle mass and force production by inhibiting ActRIIB signaling. The Smad7 gene therapy did not affect other organs, suggesting that safely targeting ActRIIB signaling is possible.


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.

View Full Text