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 comprising administering to a subject in need thereof a pharmaceutically effective amount of an agent, or combination of agents, that agonizes, reduces inhibition of, supplements the activity of, increases the levels of, and/or increases the activity of GATA-1 in the subject.
2 . The method of claim 1 , wherein prior to said administration the subject has a decreased level of GATA-1 compared to levels of GATA-1 in a reference population.
3 . A method for treating or preventing ineffective erythropoiesis in a subject in whom it has been determined has a decreased level of GATA-1 as compared to a reference population, comprising administering to said subject a pharmaceutically effective amount of an agent, or combination of agents, that agonizes, reduces inhibition of, supplements the activity of, increases the levels of, and/or increases the activity of GATA-1 in the subject.
4 . The method of claim 1 , wherein the subject has a decreased level of one or more heme biosynthesis genes selected from the group consisting of: Ppox, Fech, Alas2, and Abcb101, compared to levels of Ppox, Fech, Alas2, and Abcb101 in a reference population.
5 . The method of claim 1 , wherein the subject has a decreased level of one or more 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.
6 . The method of claim 1 , wherein the subject is a human.
7 . The method of claim 2 , wherein the reference population consists of one or more humans.
8 . The method of claim 2 , wherein the reference population consists of 1, 2, 3, 5, 10, 20, 25, 30, 50, 70, 75, 80, 90, 100, 200, 250, 500, or 1000 individuals.
9 . The method of claim 2 , wherein the reference population consists of healthy individuals.
10 . The method of claim 2 , wherein the reference population consists of people of the same gender, age, and/or weight as the subject.
11 . The method of claim 2 , wherein the reference population consists of people without ineffective erythropoiesis.
12 . The method of claim 2 , wherein the decreased level of GATA-1 is about 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 100%, 200%, or 500% lower than the levels of GATA-1 in the reference population.
13 . The method of claim 4 , wherein the decreased level of Ppox, Fech, Alas2, and Abcb101 are about 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 100%, 200%, or 500% lower than the levels of Ppox, Fech, Alas2, and/or Abcb101 in the reference population.
14 . The method of claim 5 , wherein the decreased level of KLF1, NFE2, GYPA, Bcl21, Bnip31, Bach1, and/or ANK1 are about 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 100%, 200%, or 500% lower than the levels of KLF1, NFE2, GYPA, Bcl21, Bnip31, Bach1, and/or ANK1 in the reference population.
15 . The method of claim 2 , wherein the decreased level of GATA-1 is about 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 100%, 200%, or 500% lower than the levels of GATA-1 in the bottom 10%, bottom 5%, bottom 4%, bottom 3%, bottom 2%, or bottom 1% of the reference population.
16 . The method of claim 4 , wherein the decreased level of Ppox, Fech, Alas2, and/or Abcb101 is about 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 100%, 200%, or 500% lower than the levels of Ppox, Fech, Alas2, and/or Abcb101 in the bottom 10%, bottom 5%, bottom 4%, bottom 3%, bottom 2%, or bottom 1% of the reference population.
17 . The method of claim 5 , wherein the decreased level of KLF1, NFE2, GYPA, Bcl21, Bnip31, Bach1, and/or ANK1 is about 10%, 20%, 25%, 30%, 40%, 50%, 60%, 70%, 75%, 80%, 90%, 100%, 200%, or 500% lower than the levels of KLF1, NFE2, GYPA, Bcl21, Bnip31, Bach1, and/or ANK1 in the bottom 10%, bottom 5%, bottom 4%, bottom 3%, bottom 2%, or bottom 1% of the reference population.
18 . The method of claim 1 , wherein the agent increases GATA-1 levels and/or activity in erythroblasts in the subject.
19 . The method of claim 1 , wherein the agent is tamoxifen.
20 . The method of claim 1 , wherein the agent is oestradiol.
21 - 256 . (canceled)