INHIBITION OF MYOSTATIN WITH EMPHASIS ON FOLLISTATIN AS A THERAPY FOR MUSCLE DISEASE

[Neal Johnette]

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 hgh side effects 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.

Keywords: follistatin, myostatin inhibition, muscle disease, muscle enhancement

Strategies to increase muscle size and strength through inhibition of the myostatin pathway show promise for clinical application.34 Follistatin is a potent antagonist of myostatin that takes advantage of its ability to hinder access to signaling receptors on skeletal muscle. The muscle-building properties of follistatin are well demonstrated,36 but because it is a peptide with multiple functions, concerns have been raised regarding off-target effects when considering its appropriateness for treatment of muscle disease. The goal of this review is to thoroughly discuss these complex interactions and demonstrate a strategy that takes advantage of known follistatin properties that can be harnessed to promote efficacy to increase muscle mass and muscle strength in the absence of adverse clinical effects.

Emphasis on myostatin inhibition emerges because treating muscle disorders by most pharmacologic approaches has been disappointing. Androgen steroids, popular among athletes, pose long-term risks66 including: (1) endocrine (gonadal atrophy and sterility)28; (2) somatic (changes in blood lipid profiles and cardiac hypertrophy)3,30,37; and (3) neuropsychiatric (anxiety, depression, hostility, paranoia)57; and attempts to treat muscle disorders have been disappointing.5 Glucocorticosteroids, the only beneficial drug treatment for muscular dystrophy, are virtually entirely targeted toward the Duchenne muscular dystrophy (DMD) population.46,50 Even in this patient group the mechanism of benefit is poorly understood, and the evidence that muscle mass is increased is meager.46 For genetic muscle diseases, gene manipulation strategies are on the horizon, including gene replacement,12,19,20,62 exon skipping,1,44 and mutation suppression.7,23 Despite enthusiasm, experimental studies suggest that these approaches usually fall short of returning function to normal.40 Combinational approaches that include partial correction of the underlying defect (i.e., micro-dystrophin) combined with increasing muscle size and strength appear to offer more.2 For muscle diseases where correction of the underlying defect might not be an option, increasing muscle size and strength may be opportune for both genetic and acquired muscle diseases where treatment options are limited. Examples include some forms of muscular dystrophy where gene manipulation strategies are not yet applicable (e.g., facioscapulohumeral dystrophy, FSHD), acquired disorders such as sporadic inclusion body myositis, where pharmacologic treatment failures predominate, or cachectic disorders related to cancer or aging that may be ideally suited for a muscle-enhancing approach.