Truncated Activin Type II Receptor and Methods of Use

Abstract

The present invention provides a substantially purified growth differentiation factor (GDF) receptor, including a GDF-8 (myostatin) receptor, as well as functional peptide portions thereof. In addition, the invention provides a virtual representation of a GDF receptor or a functional peptide portion thereof. The present invention also provides a method of modulating an effect of myostatin on a cell by contacting the cell with an agent that affects myostatin signal transduction in the cell. In addition, the invention provides a method of ameliorating the severity of a pathologic condition, which is characterized, at least in part, by an abnormal amount, development or metabolic activity of muscle or adipose tissue in a subject, by modulating myostatin signal transduction in a muscle cell or an adipose tissue cell in the subject. The invention also provides a method of modulating the growth of muscle tissue or adipose tissue in a eukaryotic organism by administering an agent that affects myostatin signal transduction to the organism.

1 . A pharmaceutical composition comprising a therapeutically effective amount of an Activin Receptor Type IIB (ActRIIB) polypeptide comprising the extracellular domain of ActRIIB. 
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the ActRIIB polypeptide is capable of modulating a GDF-8 activity. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the composition is formulated for oral or parenteral administration. 
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein the ActRIIB polypeptide binds to GDF-8 with a dissociation constant (Kd) of at least 1×10−6M. 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein the ActRIIB polypeptide binds to GDF-8 with a dissociation constant (Kd) of at least 1×10−7M. 
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein the ActRIIB polypeptide binds to GDF-8 with a dissociation constant (Kd) of at least 1×10−8M. 
     
     
         7 . The pharmaceutical composition of  claim 1 , wherein the ActRIIB polypeptide binds to GDF-8 with a dissociation constant (Kd) of at least 1×10−9M. 
     
     
         8 . The pharmaceutical composition of  claim 1 , wherein the ActRIIB polypeptide binds to GDF-8 with a dissociation constant (Kd) of at least 1×10−10M. 
     
     
         9 . A method for increasing muscle mass in a mammal comprising administering an effective amount of a polypeptide comprising the extracellular domain of Activin Receptor Type IIB (ActRIIB). 
     
     
         10 . The method of  claim 9 , wherein the mammal is suffering from a disease or disorder chosen from muscular disorder and neuromuscular disorder. 
     
     
         11 . The method of  claim 10 , wherein the disease or disorder is a muscular disorder. 
     
     
         12 . The method of  claim 11 , wherein the muscular disorder is chosen from at least one of muscular dystrophy, muscle atrophy, and muscle wasting disorder. 
     
     
         13 . The method of  claim 11 , wherein the muscular disorder is muscular dystrophy. 
     
     
         14 . The method of  claim 13 , wherein the muscular dystrophy is Duchenne muscular dystrophy. 
     
     
         15 . The method of  claim 11 , wherein the muscular disorder is muscle atrophy. 
     
     
         16 . The method of  claim 11 , wherein the muscular disorder is a muscle wasting disorder. 
     
     
         17 . The method of  claim 16 , wherein the muscle wasting disorder is cachexia. 
     
     
         18 . The method of  claim 16 , wherein the muscle wasting disorder is anorexia. 
     
     
         19 . The method of  claim 10 , wherein the disease or disorder is a neuromuscular disorder. 
     
     
         20 . The method of  claim 19 , wherein the neuromuscular disorder is amyotrophic lateral sclerosis (ALS). 
     
     
         21 . The method of  claim 9 , wherein the mammal is human. 
     
     
         22 . The method of  claim 9 , wherein the ActRIIB polypeptide is capable of binding to growth and differentiation factor-8 (GDF-8) and inhibiting a GDF-8 activity. 
     
     
         23 . The method of  claim 22 , wherein the ActRIIB polypeptide binds to GDF-8 with a dissociation constant (Kd) of at least 1×10−6M. 
     
     
         24 . The method of  claim 22 , wherein the ActRIIB polypeptide binds to GDF-8 with a dissociation constant (Kd) of at least 1×10−7M. 
     
     
         25 . The method of  claim 22 , wherein the ActRIIB polypeptide binds to GDF-8 with a dissociation constant (Kd) of at least 1×10−8M. 
     
     
         26 . The method of  claim 22 , wherein the ActRIIB polypeptide binds to GDF-8 with a dissociation constant (Kd) of at least 1×10−9M. 
     
     
         27 . The method of  claim 22 , wherein the ActRIIB polypeptide binds to GDF-8 with a dissociation constant (Kd) of at least 1×10−10M.