Inhibition of myostatin with emphasis on follistatin as a therapy for muscle dis

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Muscle Nerve. 2009 Mar;39(3):283-96.

Inhibition of myostatin with emphasis on follistatin as a therapy for muscle

disease.

Rodino-Klapac LR, Haidet AM, Kota J, Handy C, Kaspar BK, Mendell JR.

Center for Gene Therapy, Research Institute at Nationwide Children's Hospital,

700 Children's Drive, Columbus, Ohio 43205 USA.

In most cases, pharmacologic strategies to treat genetic muscle disorders and

certain acquired disorders, such as sporadic inclusion body myositis, have

produced modest clinical benefits. In these conditions, inhibition of the

myostatin pathway represents an alternative strategy to improve functional

outcomes.

Preclinical data that support this approach clearly demonstrate the potential

for blocking the myostatin pathway. Follistatin has emerged as a powerful

antagonist of myostatin that can increase muscle mass and strength.

Follistatin was first isolated from the ovary and is known to suppress

follicle-stimulating hormone. This raises concerns for potential adverse effects

on the hypothalamic-pituitary-gonadal axis and possible reproductive

capabilities.

In this review we demonstrate a strategy to bypass off-target effects using an

alternatively spliced cDNA of follistatin (FS344) delivered by adeno-associated

virus (AAV) to muscle. The transgene product is a peptide of 315 amino acids

that is secreted from the muscle and circulates in the serum, thus avoiding

cell-surface binding sites.

Using this approach our translational studies show increased muscle size and

strength in species ranging from mice to monkeys. Adverse effects are avoided,

and no organ system pathology or change in reproductive capabilities has been

seen.

These findings provide the impetus to move toward gene therapy clinical trials

with delivery of AAV-FS344 to increase size and function of muscle in patients

with neuromuscular disease.