Combined use of gdf traps and erythropoietin receptor activators to increase red blood cell levels
In certain aspects, the present invention provides compositions and methods for increasing red blood cell and/or hemoglobin levels in vertebrates, including rodents and primates, and particularly in humans.
1. A method for treating anemia associated with thalassemia in a subject in need thereof, wherein the subject is receiving or has received blood transfusions, wherein the method comprises administering to the subject an effective amount of a polypeptide comprising an amino acid sequence that is at least 90% identical to the sequence of amino acids 29-109 of SEQ ID NO: 1, wherein the polypeptide comprises an acidic amino acid at the position corresponding to position 79 of SEQ ID NO: 1, and wherein the polypeptide binds to GDF11 and/or myostatin.
2. The method of claim 1 , wherein the polypeptide comprises an amino acid sequence that is at least 95% identical to the sequence of amino acids 29-109 of SEQ ID NO: 1.
3. The method of claim 2 , wherein the acidic amino acid is glutamic acid.
4. The method of claim 2 , wherein the acidic amino acid is aspartic acid.
5. The method of claim 2 , wherein the polypeptide comprises an amino acid sequence that is at least 90% identical to SEQ ID NO: 28.
6. The method of claim 2 , wherein the polypeptide comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 28.
7. The method of claim 2 , wherein the polypeptide comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 28.
8. The method of claim 2 , wherein the polypeptide comprises the amino acid sequence of SEQ ID NO: 28.
9. The method of claim 1 , wherein the polypeptide comprises one or more modified amino acid residues selected from: a glycosylated amino acid, a PEGylated amino acid, a farnesylated amino acid, an acetylated amino acid, a biotinylated amino acid, an amino acid conjugated to a lipid moiety, and an amino acid conjugated to an organic derivatizing agent.
10. The method of claim 1 , wherein the polypeptide binds to GDF11.
11. The method of claim 1 , wherein the polypeptide binds to myostatin.
12. The method of claim 1 , wherein the polypeptide binds to myostatin and GDF11.
13. The method of claim 1 , wherein the polypeptide inhibits signaling by GDF11 and myostatin in a cell-based assay.
14. The method of claim 1 , wherein the polypeptide inhibits signaling by GDF11 in a cell-based assay.
15. The method of claim 1 , wherein the polypeptide inhibits signaling by myostatin in a cell-based assay.
16. The method of claim 1 , wherein the polypeptide further comprises a constant region of an immunoglobulin.
17. The method of claim 16 , wherein the constant region is derived from an IgG heavy chain.
18. The method of claim 16 , wherein the constant region of an immunoglobulin is an Fc domain.
19. The method of claim 18 , wherein the polypeptide forms a homodimer.
20. The method of claim 1 , wherein the polypeptide comprises the sequence of amino acids 29-109 of SEQ ID NO: 1, but wherein the polypeptide comprises an acidic amino acid at the position corresponding to position 79 of SEQ ID NO: 1.
21. The method of claim 1 , wherein the polypeptide comprises an amino acid sequence that is at least 90% identical to the sequence of amino acids 25-131 of SEQ ID NO: 1.
22. The method of claim 1 , wherein the polypeptide comprises an amino acid sequence that is at least 95% identical to the sequence of amino acids 25-131 of SEQ ID NO: 1.
23. The method of claim 1 , wherein the polypeptide comprises the sequence of amino acids 25-131 of SEQ ID NO: 1 , but wherein the polypeptide comprises an acidic amino acid at the position corresponding to position 79 of SEQ ID NO: 1.
24. The method of claim 1 , wherein the subject is receiving blood transfusions.