Research ArticleGene Therapy

Follistatin Gene Delivery Enhances Muscle Growth and Strength in Nonhuman Primates

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Science Translational Medicine  11 Nov 2009:
Vol. 1, Issue 6, pp. 6ra15
DOI: 10.1126/scitranslmed.3000112

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Beyond Mighty Mouse: Building Muscle Mass Strength in Monkeys

Patients with progressive neuromuscular disorders all experience the foreboding of the severe disability that awaits them and from which there is little to no relief. Although this class of disorders has multiple genetic and physiological origins, a therapy that directly addresses the debilitating muscle weakness that is the hallmark of these maladies would enhance the lives of millions. Now, in an extension of their previous work in dystrophic mice, Kota et al. describe such a therapeutic approach in preclinical studies performed in nonhuman primates. This treatment mode is applicable to several progressive neuromuscular disorders whether or not scientists have defined their precise genetic defects.

The authors used a gene therapy approach to introduce a version of the human gene encoding follistatin into the muscles of the femurs of healthy cynomolgus macaques. Follistatin is a potent inhibitor of myostatin, a signaling molecule that regulates skeletal muscle mass. Follistatin blocks myostatin signaling and augments muscle size and strength safely in mice but, until now, has not been tested in primates. Kota et al. injected a follistatin-producing gene therapy vector into the leg muscles of the monkeys and measured increases in muscle mass and strength. Sustained follistatin expression caused no aberrations in the structures or functions of a variety of organs.

This promising progress comes with some caveats. Because healthy monkeys served as subjects for this therapeutic protocol, these findings are not predictive of the outcome in a clinical setting with patients suffering from muscle disorders. In certain genetic neuromuscular diseases, the muscles undergo a repeated cycle of degeneration and regeneration. The vector used in this study does not integrate into the muscle cell genome and thus can be lost from the cells during the degeneration-regeneration cycles. However, the authors point out that the enhancement of muscle size and strength observed in similarly treated dystrophic mice persisted for more than a year even though there was appreciable muscle turnover. More study is needed before follistatin enters the clinic, such as a molecular assessment of gene and vector sequences in multiple tissues. Nonetheless, the work of Kota et al. constitutes proof of principle for the use of myostatin inhibitors to build muscle in primates.


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