Compositions and methods for treating pulmonary hypertension
In some aspects, the disclosure relates to GDF/BMP antagonists and methods of using GDF/BMP antagonists to treat, prevent, or reduce the progression rate and/or severity of pulmonary hypertension (PH), particularly treating, preventing or reducing the progression rate and/or severity of one or more PH-associated complications. The disclosure also provides methods of using a GDF/BMP antagonist to treat, prevent, or reduce the progression rate and/or severity of a variety of conditions including, but not limited to, pulmonary vascular remodeling, pulmonary fibrosis, and right ventricular hypertrophy. The disclosure further provides methods of using a GDF/BMP antagonist to reduce right ventricular systolic pressure in a subject in need thereof.
1. A method of treating pulmonary arterial hypertension, comprising administering to a patient in need thereof an effective amount of a fusion protein comprising an ActRIIA polypeptide, wherein said ActRIIA polypeptide comprises an amino acid sequence that is at least 97% identical to an amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 9, and wherein the ActRIIA polypeptide binds to activin and/or GDF11.
2. The method of claim 1 , wherein the method decreases pulmonary arterial pressure in the patient.
3. The method of claim 1 , wherein the method increases the patient's 6-minute walk distance.
4. The method of claim 1 , wherein the method decreases pulmonary vascular resistance in the patient.
5. The method of claim 1 , wherein the method delays clinical worsening of pulmonary arterial hypertension.
6. The method of claim 5 , wherein the method delays clinical worsening of pulmonary arterial hypertension in accordance with the World Health Organization's functional classification system for pulmonary hypertension.
7. The method of claim 1 , wherein the fusion protein further comprises an Fc domain of an immunoglobulin.
8. The method of claim 7 , wherein the fusion protein comprises a linker domain positioned between the ActRIIA polypeptide and the Fc domain of the immunoglobulin.
9. The method of claim 8 , wherein the ActRIIA polypeptide comprises an amino acid sequence that is at least 98% identical to an amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 9.
10. The method of claim 8 , wherein the ActRIIA polypeptide comprises an amino acid sequence that is at least 99% identical to an amino acid sequence corresponding to residues 30-110 of SEQ ID NO: 9.
11. The method of claim 1 , wherein the ActRIIA polypeptide comprises an amino acid sequence that is at least 97% identical to an amino acid sequence corresponding to residues 21-135 of SEQ ID NO: 9.
12. The method of claim 11 , wherein the fusion protein further comprises an Fc domain of an immunoglobulin.
13. The method of claim 12 , wherein the fusion protein comprises a linker domain positioned between the ActRIIA polypeptide and the Fc domain of the immunoglobulin.
14. The method of claim 13 , wherein the ActRIIA polypeptide comprises an amino acid sequence that is at least 98% identical to an amino acid sequence corresponding to residues 21-135 of SEQ ID NO: 9.
15. The method of claim 13 , wherein the ActRIIA polypeptide comprises an amino acid sequence that is at least 99% identical to an amino acid sequence corresponding to residues 21-135 of SEQ ID NO: 9.
16. The method of claim 1 , wherein the ActRIIA polypeptide comprises an amino acid sequence that is at least 97% identical to the amino acid sequence of SEQ ID NO: 10.
17. The method of claim 16 , wherein the fusion protein further comprises an Fc domain of an immunoglobulin.
18. The method of claim 17 , wherein the fusion protein comprises a linker domain positioned between the ActRIIA polypeptide and the Fc domain of the immunoglobulin.
19. The method of claim 18 , wherein the ActRIIA polypeptide comprises an amino acid sequence that is at least 98% identical to the amino acid sequence of SEQ ID NO: 10.
20. The method of claim 18 , wherein the ActRIIA polypeptide comprises an amino acid sequence that is at least 99% identical to the amino acid sequence of SEQ ID NO: 10.
21. The method of claim 1 , wherein the ActRIIA polypeptide comprises an amino acid sequence that is at least 97% identical to the amino acid sequence of SEQ ID NO: 11.
22. The method of claim 21 , wherein the fusion protein further comprises an Fc domain of an immunoglobulin.
23. The method of claim 22 , wherein the fusion protein comprises a linker domain positioned between the ActRIIA polypeptide and the Fc domain of the immunoglobulin.
24. The method of claim 23 , wherein the ActRIIA polypeptide comprises an amino acid sequence that is at least 98% identical to the amino acid sequence of SEQ ID NO: 11.
25. The method of claim 23 , wherein the ActRIIA polypeptide comprises an amino acid sequence that is at least 99% identical to the amino acid sequence of SEQ ID NO: 11.
26. The method of claim 8 , wherein the fusion protein is a homodimer.