Methods of increasing endogenous erythropoietin (EPO)

Abstract

The present invention relates to methods for treating erythropoietin-associated conditions by increasing endogenous erythropoietin in vitro and in vivo. Methods for treating, pretreating or preconditioning, or preventing erythropoietin-associated conditions are also included. Compounds for use in these methods are provided, as are methods of identifying such compounds.

What is claimed is:  
     
         1 . A method for increasing endogenous erythropoietin (EPO) in a subject, the method comprising stabilizing the alpha subunit of hypoxia inducible factor (HIFα).  
     
     
         2 . A method for increasing endogenous EPO in a subject, the method comprising inhibiting hydroxylation of HIFα.  
     
     
         3 . A method for increasing endogenous EPO in a subject, the method comprising inhibiting 2-oxoglutarate dioxygenase enzyme activity.  
     
     
         4 . A method for increasing endogenous EPO levels in a subject, the method comprising inhibiting HIF prolyl hydroxylase enzyme activity.  
     
     
         5 . The method of  claim 1 , wherein HIFα is selected from the group consisting of HIF-1α, HIF-2α, HIF-3α, and any fragment thereof.  
     
     
         6 . The method of  claim 1 , wherein the HIFα is endogenous to the subject.  
     
     
         7 . The method of  claim 3 , wherein the 2-oxoglutarate dioxygenase enzyme is selected from the group consisting of EGLN1, EGLN2, EGLN3, procollagen prolyl 4-hydroxylase, procollagen prolyl 3-hydroxylase, procollagen lysyl hydroxylase, PHD4, FIH-1, and any subunit or fragment thereof.  
     
     
         8 . The method of  claim 4 , wherein the HIF prolyl hydroxylase enzyme is selected from the group consisting of EGLN1, EGLN2, EGLN3, and any subunit or fragment thereof.  
     
     
         9 . The method of  claim 1 , wherein the method comprises administering a compound that increases endogenous EPO.  
     
     
         10 . A method for treating, preventing, or pretreating an EPO-associated disorder in a subject, the method comprising increasing endogenous EPO.  
     
     
         11 . A method for treating, preventing, or pretreating an EPO-associated disorder in a subject, the method comprising stabilizing HIFα.  
     
     
         12 . A method for treating, preventing, or pretreating an EPO-associated disorder in a subject, the method comprising inhibiting hydroxylation of HIFα.  
     
     
         13 . A method for treating, preventing, or pretreating an EPO-associated disorder in a subject, the method comprising inhibiting 2-oxoglutarate dioxygenase enzyme activity.  
     
     
         14 . A method for treating, preventing, or pretreating an EPO-associated disorder in a subject, the method comprising inhibiting HIF prolyl hydroxylase enzyme activity.  
     
     
         15 . A method for treating, preventing, or pretreating anemia in a subject, the method comprising increasing endogenous EPO.  
     
     
         16 . The method of  claim 15 , wherein the method comprises stabilizing HIFα.  
     
     
         17 . The method of  claim 15 , wherein the method comprises inhibiting 2-oxoglutarate dioxygenase enzyme activity.  
     
     
         18 . The method of  claim 15 , wherein the method comprises inhibiting HIF prolyl hydroxylase enzyme activity.  
     
     
         19 . The method of  claim 15 , wherein the anemia is associated with abnormal hemoglobin or erythrocytes.  
     
     
         20 . The method of  claim 15 , wherein the anemia is associated with a condition selected from the group consisting of diabetes, cancer, ulcers, kidney disease, immunosuppressive disease, infection, and inflammation.  
     
     
         21 . The method of  claim 15 , wherein the anemia is associated with a procedure or treatment selected from the group consisting of radiation therapy, chemotherapy, dialysis, and surgery.  
     
     
         22 . The method of  claim 15 , wherein the anemia is associated with blood loss.  
     
     
         23 . The method of  claim 22 , wherein the blood loss is associated with bleeding disorders, trauma, injury, or surgery.  
     
     
         24 . The method of  claim 15 , wherein the anemia is associated with defects in iron transport, processing, or utilization.  
     
     
         25 . The method of  claim 15 , further comprising administering to the subject a compound selected from the group consisting of an iron supplement, vitamin B 12 , folic acid, exogenous erythropoietin, and granulocyte-colony stimulating factor.  
     
     
         26 . A method for treating, preventing, or pretreating a neurological disorder in a subject, the method comprising increasing endogenous EPO.  
     
     
         27 . The method of  claim 26 , the method comprising stabilizing HIFα.  
     
     
         28 . The method of  claim 26 , the method comprising inhibiting 2-oxoglutarate dioxygenase enzyme activity.  
     
     
         29 . The method of  claim 26 , the method comprising inhibiting HIF prolyl hydroxylase enzyme activity.  
     
     
         30 . The method of  claim 26 , wherein the neurological disorder is associated with a condition selected from the group consisting of stroke, trauma, epilepsy, and neurodegenerative disease.  
     
     
         31 . A method for enhancing oxygen consumption in a subject, the method comprising increasing endogenous EPO.  
     
     
         32 . The method of  claim 9 , wherein the compound stabilizes HIFα.  
     
     
         33 . The method of  claim 9 , wherein the compound inhibits hydroxylation of HIFα.  
     
     
         34 . The method of  claim 9 , wherein the compound inhibits 2-oxoglutarate dioxygenase enzyme activity.  
     
     
         35 . The method of  claim 9 , wherein the compound inhibits HIF prolyl hydroxylase enzyme activity.  
     
     
         36 . The method of  claim 9 , wherein the compound is selected from the group consisting of heterocyclic carboxamides, phenanthrolines, hydroxamates, and physiologically active salts and prodrugs derived therefrom.  
     
     
         37 . The method of  claim 36 , wherein the heterocyclic carboxamides are selected from the group consisting of pyridine carboxamides, quinoline carboxamides, isoquinoline carboxamides, cinnoline carboxamides, and beta-carboline carboxamides.  
     
     
         38 . The method of  claim 9 , wherein the compound is delivered in an oral formulation.  
     
     
         39 . The method of  claim 9 , wherein the compound is delivered in a trasnsdermal formulation.  
     
     
         40 . A method for identifying a compound that increases endogenous EPO, the method comprising: 
 (a) administering a compound to a subject;    (b) measuring EPO in the subject or in a sample from the subject; and    (c) comparing the EPO in the subject or in the sample to a standard, wherein an increase in the EPO in the subject or in the sample relative to the standard is indicative of a compound that increases endogenous EPO.    
     
     
         41 . The method of  claim 1 , wherein the stabilizing is in vivo.  
     
     
         42 . The method of  claim 1 , wherein the stabilizing is in vitro.  
     
     
         43 . The method of  claim 1 , wherein the subject is an animal.  
     
     
         44 . The method of  claim 1 , wherein the subject is mammal.  
     
     
         45 . The method of  claim 1 , wherein the subject is a human.  
     
     
         46 . The method of  claim 1 , wherein the subject is a cell.