Novel Therapeutic Approaches for Inclusion Body Myositis

Thomas E. Lloyd


Curr Opin Rheumatol. 2010;22(6):658-664. 

In This Article

Myostatin Inhibition

During vertebrate development, one of the critical regulators of muscle growth is the myostatin pathway. Myostatin is a member of the transforming growth factor (TGF)-beta family of secreted growth factors and is a potent suppressor of muscle growth. Myostatin knockout mice have a two-fold to three-fold increase in muscle mass, without abnormalities in other organs such as the heart.[5] This pathway is clearly important in humans, as patients with a loss-of-function mutation in myostatin have marked muscle hypertrophy and increased strength.[6] Thus, inhibitors of myostatin may be potent stimulators of muscle growth.

Myostatin is synthesized as a prepropeptide and forms a homodimer via a covalent disulfide bond. After cleavage extracellularly, the amino-terminal proprotein remains noncovalently attached to the carboxy-terminal peptide, keeping it in an inactive state. A second cleavage event by a metalloproteinase activates myostatin, allowing it to bind to its receptor, activin receptor type IIB (ActRIIB). Myostatin can be inactivated by binding to proteins including follistatin, follistatin-related gene (FLRG) and GASP-1. Activation of ActRIIB leads to activation of a Smad complex that enters the nucleus and activates the transcription of myogenic genes, inhibiting both the proliferation and differentiation of myogenic precursors.

Most myostatin inhibitors in development bind to myostatin extracellularly and reduce its bioavailability. For example, an antibody against myostatin, MYO-029, was used in a double-blind, placebo-controlled phase I clinical trial in 116 adult muscular dystrophy patients.[7] Although the study was not powered to evaluate clinical efficacy, this drug was well tolerated, with the major side effect being a cutaneous hypersensitivity reaction at high doses. Other companies are developing a soluble ActRIIB protein that can similarly bind to and inactivate myostatin.[8•] sActRIIB has been shown to be very effective in mouse muscular dystrophy models.[9] Other therapies in development include the propeptide that keeps myostatin inactive[10] and a dominant-negative myostatin analog.[11]

One of the most promising myostatin inhibitors in development is follistatin.[12•] Follistatin binds to and inhibits myostatin and other TGF-beta family members such as activin. Interestingly, muscle-specific overexpression of follistatin causes an even greater increase in muscle mass than the myostatin knockout mouse,[13] suggesting that in addition to inhibition of myostatin, follistatin also acts to increase muscle growth independently of myostatin. Indeed, follistatin overexpression in myostatin knockout mice causes a quadrupling of muscle mass.[14]

Mendell and colleagues utilized the natural propensity of the AAV virus to infect muscle cells to overexpress the follistatin (FSTN) gene in animal models. AAV gene vectors have proven to be safe, and a single injection can lead to lifelong expression of the gene of interest. Injection of AAV-FSTN into muscles of wild-type mice led to a two-fold increase in muscle size, and even had efficacy in uninjected muscles, demonstrating that it is released into the circulation.[15] Furthermore, AAV-FSTN has a long-term benefit in the mouse muscular dystrophy models when injected into the quadriceps muscle.[15] A recent study in nonhuman primates injected with AAV-FSTN into the quadriceps muscle showed a long-term, marked increase in muscle size without adverse effects.[16••] An alternative approach to gene therapy is to upregulate follistatin expression. Indeed, histone deacetylase inhibitors upregulate follistatin and show efficacy in mouse models of muscular dystrophy.[17,18]

One concern regarding follistatin therapy is a potential adverse effect on fertility (it was initially discovered as an inhibitor of FSH secretion). However, an alternatively spliced isoform of follistatin containing the carboxy-terminus (named FS-344) inhibits the ability of follistatin to bind activin, and thus has little effect on reproduction in mouse or monkey animal models.[15,16••] A potentially beneficial side-effect of follistatin therapy in myositis is an anti-inflammatory effect.[19]


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