Methods for increasing red blood cell levels and treating ineffective erythropoiesis
In certain aspects, the present disclosure provides compositions and methods for increasing red blood cell and/or hemoglobin levels in a subject in need thereof. Subjects in need include, for example, subjects having anemia and/or ineffective erythropoiesis as a result of having reduced GATA-1, heat shock factor and/or NFE2 levels as compared to the levels in a reference population.
1. A method for treating or preventing ineffective erythropoiesis in a subject in need thereof, the method comprising:
i) determining the level of GATA-1 in the subject;
ii) identifying the subject who has a decreased level of GATA-1 as compared to a reference population; and
iii) administering to the subject identified in ii) a pharmaceutically effective amount of an agent, or combination of agents, selected from the group consisting of an ActRIIA polypeptide comprising a sequence that is at least 90% identical to the amino acid sequence corresponding to positions 21-135 of SEQ ID NO: 9, and an ActRIIB polypeptide comprising a sequence that is at least 90% identical to the amino acid sequnce corresponding to positions 29-109 of SEQ ID NO: 1,
wherein the ActRIIA and ActRIIB polypeptides are capable of binding to GDF11; and wherein the reference population consists of people without ineffective erythropoiesis.
2. The method of claim 1 , wherein the subject has a decreased level of one or more:
a) heme biosynthesis genes selected from the group consisting of: Ppox, Fech, Alas2, and Abcb10, compared to levels of Ppox, Fech, Alas2, and Abcb10 in a reference population; and/or
b) erythroid differentiation factors selected from the group consisting of: KLF1, NFE2, GYPA, Bcl21, Bnip31, Bach1, and ANK1, compared to levels of KLF1, NFE2, GYPA, Bcl21, Bnip31, Bach1, and ANK1 in a reference population.
3. The method of claim 1 , wherein the reference population consists of healthy individuals.
4. The method of claim 1 , wherein the agent agonizes, reduces the inhibition of, supplements the activity of, increases the levels of and/or increases the activity of one or more:
a) heme biosynthesis genes selected from the group consisting of: Ppox, Fech, Alas2, and Abcb 10; and/or
b) erythroid differentiation factors selected from the group consisting of: KLF1, NFE2, GYPA, Bcl21, Bnip31, Bach1, and ANK1.
5. The method of claim 1 , wherein the agent is an ActRIIA polypeptide comprising an amino acid sequence that is at least 90% identical to the sequence of amino acids 21-135 of SEQ ID NO: 9.
6. The method of claim 1 , wherein the agent is an ActRIIA polypeptide comprising an amino acid sequence that is at least 95% identical to SEQ ID NO: 10.
7. The method of claim 1 , wherein the agent is an ActRIIA polypeptide comprising the amino acid sequence of SEQ ID NO: 10.
8. The method of claim 1 , wherein the agent is an ActRIIB 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.
9. The method of claim 1 , wherein the agent is an ActRIIB polypeptide comprising an amino acid sequence that is at least 90% identical to the amino acid sequence corresponding to positions 25-131 of SEQ ID NO: 1.
10. The method of claim 1 , wherein the agent is an ActRIIB polypeptide comprising an amino acid sequence that is at least 95% identical to the amino acid sequence corresponding to positions 25-131 of SEQ ID NO: 1.
11. The method of claim 1 , wherein the agent is an ActRIIB polypeptide comprising the amino acid sequence corresponding to positions 25-131 of SEQ ID NO: 1.
12. The method of claim 1 , wherein the agent is an ActRIIA polypeptide comprising a polypeptide selected from:
a) a polypeptide comprising the amino acid sequence of SEQ ID NO: 32 or comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 32; and
b) a polypeptide comprising the amino acid sequence of SEQ ID NO: 36 or comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 36.
13. The method of claim 1 , wherein the agent is an ActRIIB polypeptide comprising a polypeptide selected from:
a) a polypeptide comprising the amino acid sequence of SEQ ID NO: 40 or comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 40;
b) a polypeptide comprising the amino acid sequence of SEQ ID NO: 41 or comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 41;
c) a polypeptide comprising the amino acid sequence of SEQ ID NO: 44 or comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 44;
d) a polypeptide comprising the amino acid sequence of SEQ ID NO: 46 or comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 46;
e) a polypeptide comprising the amino acid sequence of SEQ ID NO: 50 or comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 50;
f) a polypeptide comprising the amino acid sequence of SEQ ID NO: 78 or comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 78;
g) a polypeptide comprising the amino acid sequence of SEQ ID NO: 61 or comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 61;
h) a polypeptide comprising the amino acid sequence of SEQ ID NO: 64 or comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 64; and
i) a polypeptide comprising the amino acid sequence of SEQ ID NO: 79 or comprising an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 79.
14. The method of claim 1 , wherein the agent is an ActRIIB polypeptide comprising an amino acid sequence that is at least 90% identical to SEQ ID NO: 64.
15. The method of claim 1 , wherein the agent is an ActRIIB polypeptide comprising an amino acid sequence that is at least 95% identical to SEQ ID NO: 64.
16. The method of claim 1 , wherein the agent is an ActRIIB polypeptide comprising the amino acid sequence of SEQ ID NO: 64.
17. The method of claim 1 , wherein the subject has myelodysplastic syndrome (MDS).
18. The method of claim 1 , wherein the ineffective erythropoiesis is associated with a hemoglobinopathy.
19. The method of claim 18 , wherein the hemoglobinopathy is a thalassemia selected from the group consisting of: alpha-thalassemia-minima, alpha-thalassemia minor, Hemoglobin H disease, alpha-thalassemia major, beta-thalassemia-minor, beta-thalassemia intermedia, beta-thalassemia major, Hemoglobin E disease, and delta-beta-thalassemia.
20. The method of claim 18 , wherein the hemoglobinopathy is selected from the group consisting of: sickle-cell anemia, Hemoglobin C disease, and hemoglobin S-C disease.