Follistatin domain containing proteins

Abstract

The present invention relates to the use of proteins comprising at least one follistatin domain to modulate the level or activity of growth and differentiation factor-8 (GDF-8). More particularly, the invention relates to the use of proteins comprising at least one follistatin domain, excluding follistatin itself, for treating disorders that are related to modulation of the level or activity of GDF-8. The invention is useful for treating muscular diseases and disorders, particularly those in which an increase in muscle tissue would be therapeutically beneficial. The invention is also useful for treating diseases and disorders related to metabolism, adipose tissue, and bone degeneration.

1 - 47 . (canceled) 
     
     
         48 . A method of increasing muscle mass or muscle strength in a mammal in need thereof, comprising: administering a therapeutically effective amount of at least one protein comprising at least one follistatin domain, wherein the at least one follistatin domain is from a protein other than follistatin, thereby increasing muscle mass or muscle strength. 
     
     
         49 . A method of treating a muscular disease or disorder associated with GDF-8, comprising: administering a therapeutically effective amount of at least one protein comprising at least one follistatin domain, wherein the at least one follistatin domain is from a protein other than follistatin, thereby treating the muscular disease or disorder. 
     
     
         50 . The method of  claim 48  or  claim 49 , wherein the protein is chosen from FRP, agrins, osteonectin, hevin, IGFBP7, U19878 and GASP2. 
     
     
         51 . The method of  claim 48  or  claim 49 , wherein the protein has a stabilizing modification. 
     
     
         52 . The method of  claim 51 , wherein the modification is a fusion to the Fc region of an IgG molecule. 
     
     
         53 . The method of  claim 52 , wherein the IgG molecule is IgG1 or IgG4, or a derivative of IgG1 or of IgG4. 
     
     
         54 . The method of  claim 52 , wherein the IgG molecule is IgG1 or a derivative thereof. 
     
     
         55 . The method of  claim 52 , wherein the IgG molecule is fused to the protein comprising at least one follistatin domain by a linker peptide. 
     
     
         56 . The method of  claim 51 , wherein the modification comprises an altered glycosylation site. 
     
     
         57 . The method of  claim 51 , wherein the modification comprises at least one carbohydrate moiety. 
     
     
         58 . The method of  claim 51 , wherein the protein is linked to albumin or an albumin derivative. 
     
     
         59 . The method of  claim 51 , wherein the modification comprises a nonproteinaceous polymer. 
     
     
         60 . The method of  claim 51 , wherein the modification comprises pegylation. 
     
     
         61 . The method of  claim 49 , wherein the muscular disease or disorder is muscular dystrophy. 
     
     
         62 . The method of  claim 61 , wherein the muscular dystrophy is chosen from severe or benign X-linked muscular dystrophy, limb-girdle dystrophy, facioscapulohumeral dystrophy, myotonic dystrophy, distal muscular dystrophy, progressive dystrophic opthalmoplegia, oculopharyngeal dystrophy, and Fakuyama-type congenital muscular dystrophy. 
     
     
         63 . The method of  claim 49 , wherein the muscular disease or disorder is chosen from congenital myopathy, myotonia congenital, familial periodic paralysis, paroxysmal myoglobinuria, myasthenia gravis, Eaton-Lambert syndrome, secondary myasthenia, paroxymal muscle atrophy, muscle wasting syndrome, sarcopenia, and cachexia. 
     
     
         64 . The method of  claim 49 , wherein the disorder is a muscular disorder chosen from a traumatic injury to muscle tissue and a chronic injury to muscle tissue. 
     
     
         65 . The method of  claim 48  or  claim 49 , wherein the protein is administered at one time, or at daily, weekly, or monthly intervals. 
     
     
         66 . The method of  claim 48  or  claim 49 , wherein the protein is administered at a dose of from 5 mg to 100 mg. 
     
     
         67 . The method of  claim 48  or  claim 49 , wherein the protein is administered at a dose of from 15 mg to 85 mg. 
     
     
         68 . The method of  claim 48  or  claim 49 , wherein the protein is administered at a dose of from 3 mg to 70 mg. 
     
     
         69 . The method of  claim 48  or  claim 49 , wherein the protein is administered at a dose of from 40 mg to 60 mg. 
     
     
         70 . The method of  claim 62 , wherein the muscular dystrophy is severe X-linked muscular dystrophy. 
     
     
         71 . The method of  claim 62 , wherein the muscular dystrophy is benign X-linked muscular dystrophy. 
     
     
         72 . The method of  claim 62 , wherein the muscular dystrophy is limb-girdle dystrophy. 
     
     
         73 . The method of  claim 62 , wherein the muscular dystrophy is facioscapulohumeral dystrophy. 
     
     
         74 . The method of  claim 62 , wherein the muscular dystrophy is myotonic dystrophy. 
     
     
         75 . The method of  claim 62 , wherein the muscular dystrophy is distal muscular dystrophy. 
     
     
         76 . The method of  claim 62 , wherein the muscular dystrophy is progressive dystrophic opthalmoplegia. 
     
     
         77 . The method of  claim 62 , wherein the muscular dystrophy is oculopharyngeal dystrophy. 
     
     
         78 . The method of  claim 62 , wherein the muscular dystrophy is Fakuyama-type congenital muscular dystrophy. 
     
     
         79 . The method of  claim 63 , wherein the disorder is congenital myopathy. 
     
     
         80 . The method of  claim 63 , wherein the disorder is myotonia congenital. 
     
     
         81 . The method of  claim 63 , wherein the disorder is familial periodic paralysis. 
     
     
         82 . The method of  claim 63 , wherein the disorder is paroxysmal myoglobinuria. 
     
     
         83 . The method of  claim 63 , wherein the disorder is myasthenia gravis. 
     
     
         84 . The method of  claim 63 , wherein the disorder is Eaton-Lambert syndrome. 
     
     
         85 . The method of  claim 63 , wherein the disorder is secondary myasthenia. 
     
     
         86 . The method of  claim 63 , wherein the disorder is paroxymal muscle atrophy. 
     
     
         87 . The method of  claim 63 , wherein the disorder is muscle wasting syndrome. 
     
     
         88 . The method of  claim 63 , wherein the disorder is sarcopenia. 
     
     
         89 . The method of  claim 63 , wherein the disorder is cachexia.