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

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Muscle Nerve. 2009 Feb 10;39(3):283-296.

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.