This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This is a randomized, placebo-controlled, multiple ascending dose safety study of an inhibitor of myostatin for adult muscular dystrophy, sponsored by Wyeth. Muscular dystrophy (MD) comprises a group of distinct inherited degenerative muscular disorders characterized by progressive muscle weakness and wasting of variable muscle groups with variable severity. The genes and protein products that cause Becker muscular dystrophy (BMD) and most forms of limb-girdle muscular dystrophy (LGMD) disorders have been identified, and this information helps establish an accurate diagnosis. In facioscapulohumeral muscular dystrophy (FSHD), a chromosome 4q deletion is highly specific for diagnosis. Available treatment options are inadequate as there is currently no approved drug, cure, or long-term effective treatment for any type of muscular dystrophy. Growth and Differentiation Factor-8 (GDF-8), also known as myostatin, is a member of the transforming growth factor- beta (TGF-?) superfamily of secreted growth factors and appears to be a specific negative regulator of skeletal muscle mass. GDF-8 is unique among the TGF-? superfamily because its expression is almost exclusively restricted to cells of skeletal muscle lineage. Mice genetically deficient in GDF-8 (GDF-8 knockout mice) have 2 to 3-fold greater muscle mass than their wild type littermates. The increased muscle mass is the result of fiber hypertrophy and hyperplasia. In addition, the GDF-8 knockout mice accumulate less fat than their wild type littermates, which may be a secondary consequence of increased muscle mass since a similar effect is seen in other genetic models of muscle hypertrophy. Aside from having increased muscle and decreased fat, the GDF-8 knockout mice appear normal and healthy. GDF-8 is highly conserved in sequence and in function across species. There are several naturally occurring GDF-8 mutations in cattle, which have been linked to the double-muscled phenotype. The amino acid sequence of murine and human GDF-8 is identical, as is the pattern of mRNA expression. A hypermuscular child with a myostatin mutation has recently been identified. This conservation of sequence and function suggests that inhibition of GDF-8 in humans is likely to have an effect similar to that of inhibition of GDF-8 in mice. Given its positive effect on skeletal muscle mass and the absence of pathology in knockout mice, GDF-8 represents an attractive target for disorders associated with muscle wasting. MYO-029 is a recombinant human antibody that has a high affinity for binding to GDF-8 and inhibiting its activity. The results of pharmacology studies in mice with severe combined immunodeficiency disease (SCID) have demonstrated that treatment with MYO-029 increases skeletal muscle mass by up to 30% and increases forelimb grip strength. The effect on muscle mass was dosage and time dependent, and dosages as low as 1 mg/kg/week were efficacious when given for 12 weeks. The increase in mass was specific to skeletal muscle, and was the result of fiber hypertrophy and not hyperplasia. The increase in mass was also reversible by 20 weeks after treatment was discontinued. The effect of MYO-029 on skeletal muscle was observed in both male and female mice and in sexually mature mice that are either still growing or no longer growing. Based on the preclinical results described above, Wyeth is conducting a safety study of MYO-029 in the muscular dystrophies that occur in adults: BMD, FSHD, and LGMD.
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