Methods for increasing red blood cell levels and treating ineffective erythropoiesis

Abstract

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)