Truncated activin type II receptor and methods of use
View Patent ↗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 method for increasing skeletal muscle mass in a mammal in need thereof, comprising administering an effective amount of a polypeptide consisting of an extracellular domain of an Activin Receptor Type IIB (ActRIIB), wherein the polypeptide is a dominant negative form of the ActRIIB, and wherein the ActRIIB polypeptide specifically binds to growth and differentiation factor-8 (GDF-8) and inhibits GDF-8 mediated ActRIIB signal transduction.
2. The method of claim 1 , wherein the mammal is suffering from a disease or disorder chosen from muscular disorder and neuromuscular disorder.
3. The method of claim 2 , wherein the disease or disorder is a muscular disorder.
4. The method of claim 3 , wherein the muscular disorder is chosen from at least one of muscular dystrophy, muscle atrophy, and muscle wasting disorder.
5. The method of claim 3 , wherein the muscular disorder is muscular dystrophy.
6. The method of claim 5 , wherein the muscular dystrophy is Duchenne muscular dystrophy.
7. The method of claim 3 , wherein the muscular disorder is muscle atrophy.
8. The method of claim 3 , wherein the muscular disorder is a muscle wasting disorder.
9. The method of claim 8 , wherein the muscle wasting disorder is cachexia.
10. The method of claim 8 , wherein the muscle wasting disorder is anorexia.
11. The method of claim 2 , wherein the disease or disorder is a neuromuscular disorder.
12. The method of claim 11 , wherein the neuromuscular disorder is amyotrophic lateral sclerosis (ALS).
13. The method of claim 1 , wherein the mammal is human.
14. The method of claim 1 , wherein the ActRIIB polypeptide binds to GDF-8 with a dissociation constant (Kd) of at least 1×10 −6 M.
15. The method of claim 1 , wherein the ActRIIB polypeptide binds to GDF-8 with a dissociation constant (Kd) of at least 1 ×10 −7 M.
16. The method of claim 1 , wherein the ActRIIB polypeptide binds to GDF-8 with a dissociation constant (Kd) of at least 1 ×10 −8 M.
17. The method of claim 1 , wherein the ActRIIB polypeptide binds to GDF-8 with a dissociation constant (Kd) of at least 1 ×10 −9 M.
18. The method of claim 1 , wherein the ActRIIB polypeptide binds to GDF-8 with a dissociation constant (Kd) of at least 1 ×10 −10 M.
19. The method of claim 1 , wherein the dominant negative form of the ActRIIB is a soluble form of the ActRIIB extracellular domain.