making muscle wasting history

Follistatin-344 is a hormone-like protein consisting of a chain of 344 amino acids which is activated to follistatin-315 by splitting off 29 amino acids from its carboxyl end. Follistatin-315 together with two other similar proteins, follistatin-related protein (FLRG) and the growth and differentiation factor-associated serum protein-1 (GASP-1) are involved in regulating the activity of myostatin directly by blocking activin, its receptor, and indirectly also by other, still unknown reaction pathways.

Asst. Prof. Brian Kaspar of the Nationwide Children’s Hospital and The Ohio State University in Columbus, Ohio and his colleagues transferred the three genes for human follistatin-344, FLRG and GASP-1 with AAV-type-1 vectors locally into single muscles, quadriceps and tibialis anterior, of normal and mdx mice. For comparison, green fluorescent protein was transferred under the same conditions. Injection of 100 billion (1011) AAV1 vectors into 4- week old normal mice resulted, after 725 days (almost 2years), in an increase of body mass with an observable gross enhancement of muscles not only in those injected, but in others like the triceps also, meaning that this rather local treatment was able to affect other muscles as well.

The general muscle force of the entire animal was increased, as measured by the functional grip strength test. To test an approach more meaningful to a later treatment of Duchenne boys, similar experiments were done with mdx mice using single doses of either 10 or 100 billion virus particles. These dystrophic mice were either three weeks old when injected and then evaluated after five months, or – and this is very important for a later application of this technique to older Duchenne patients – they were injected once when they were 210 days old (seven months), when they already had significant symptoms of their disease, and then followed until they were 560 days old (about 1½ years). 60 days after the injection, they showed increased muscle strength which persisted until the end of the study.

In all these experiments, no obvious safety problems appeared with the virus material or with the therapeutic proteins, follistatin and the other two. The result were robust muscles with increased muscle fiber size, reduced inflammation, and less fibrosis compared to the controltreated mdx mice.

Prof. Kaspar‘s team finished their publication with the words: “The striking ability of follistatin to provide gross and functional long-term improvement to dystrophic muscles in aged animals warrants its consideration for clinical development to treat musculoskeletal diseases, including older Duchenne patients”.