Antisense approaches to counter skeletal muscle atrophy and fibrosis: targeting myostatin and other strategies

Myostatin, a secreted growth factor of the TGFb family, is expressed
in skeletal muscle and adipose tissue. Myostatin expression limits
the size of muscle during development, and myostatin mutant
animals exhibit dramatic increases in muscle mass, reduction in fat
mass and resistance to diet-induced and genetic obesity. Inhibition
of the myostatin pathway represents a potential therapeutic target
to reverse muscle wasting in a range of disease situations such
as muscular dystrophies and atrophies, sarcopenia, and diseaseinduced
(COPD, cancer, diabetes) muscle cachexia. Use of blocking
antibodies, and of natural or engineered inhibitory binding partners
to myostatin such as myostatin propeptide, follistatin and soluble
ActRIIB receptor fragments has resulted in increase in muscle mass.
These protein delivery strategies are expensive, require repeated dosing,
lead to fluctuating levels of active circulating reagent,
and can be accompanied by undesirable immune responses.
Another method to deliver these therapeuics is via gene therapy,
involving the use of non-viral or viral vectors to provide a long
term gene-based expression of myostatin inhibitors. Finally, there
are oligonucleotide-based strategies to knock-down myostain via
RNA interference or antisense mechanisms. Exon skipping is one
antisense strategy for knocking down targeted transcripts, by
interference with the natural pre-mRNA splicing pattern. We have
designed, and evaluated the use of, antisense oligonucleotides of
2O-methyl phosphorothioate and phosphodiamidate morpholino
chemistry targeting the myostatin pre-mRNA to perturb its splicing
and provide a mechanism to efficiently inhibit myostatin gene
expression activity.