Protection, restoration and enhancement of erythropoietin responsive cells, tissues and organs

Abstract

Methods and compositions are provided for protecting or enhancing an erythropoietin-responsive cell, tissue, organ or body part function or viability in vivo, in situ or ex vivo in mammals, including human beings, by systemic or local administration of an erythropoietin receptor activity modulator, such as an erythropoietin or a modified erythropoietin.

1 .- 57 . (canceled) 
     
     
         58 . A method for protecting, maintaining, enhancing or restoring the function or viability of an erythropoietin-responsive mammalian cell, or its associated cells, tissues, or organs, comprising administering to a mammal a pharmaceutical composition comprising a therapeutically effective amount of an erythropoietin having at least one of the following modifications:
 i) 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 sialic acid moieties;   ii) a reduced number or no N-linked carbohydrates;   iii) one or more modified lysine residues; or   iv) a modification of the N-terminal amino group of the erythropoietin molecule,   
       wherein the modified erythropoietin has (a) tissue protective activity as determined in vitro by the P19 assay or in vivo by the middle cerebral artery lesion assay and (b) a reduced level of erythropoietic activity compared to native erythropoietin, and wherein said mammalian cell or its associated cells, tissues, or organs is central nervous system or peripheral nervous system cells, tissues, or organs. 
     
     
         59 . The method of  claim 58  wherein a lysine residue of said modified erythropoietin is carbamylated. 
     
     
         60 . The method of  claim 58  wherein said modified erythropoietin is asialoerythropoietin. 
     
     
         61 . The method of  claim 58  wherein said modified erythropoietin is non-erythropoietic. 
     
     
         62 . The method of  claim 58  wherein said modified erythropoietin is effective for the maintenance, restoration, or enhancement of cognitive function in a mammal having or at risk for cognitive dysfunction. 
     
     
         63 . The method of  claim 62  wherein said cognitive dysfunction is caused by brain trauma. 
     
     
         64 . The method of  claim 62  wherein said enhancement of cognitive function is enhancement of learning. 
     
     
         65 . The method of  claim 58  wherein the mammal has, has had, is at risk for, or is undergoing, a seizure disorder, multiple sclerosis, stroke, central nervous system injury, neuronal loss, ischemia, cerebral ischemia, focal ischemia, subarachnoid bleeds, aneurysm, aneurismal bleeds, inflammation, age-related loss of cognitive function, neurodegenerative disease or disorder, Alzheimer's disease, Parkinson's disease, Huntington's disease, Tourette's syndrome, Leigh disease, Guillain Barre, dementia, AIDS dementia, senile dementia, Lewy body dementia, memory loss, amyotrophic lateral sclerosis, alcoholism, neuropsychiatric or neuropsychologic disorder, mood disorder, uni-polar affective disorder, depression, major depressive disorder, dysthymic disorder, mania, bipolar affective disorder, anxiety disorder, anxiety, schizophrenia, schizoaffective disorder, obsessive-compulsive disorder, attention deficit disorder, attention-deficit hyperactivity disorder, autism, a prion disease such as Creutzfeldt-Jakob disease, Friedreich's ataxia, Wilson's disease, trauma, brain trauma, blunt trauma, concussive injury, brain or spinal cord injury, post-operative cognitive dysfunction, post-operative treatment for embolic or ischemic injury, diabetic neuropathy, loss of cognitive function, neurotoxicity, subdural hematoma, muscular dystrophy, myotonic dystrophy, or panic disorder. 
     
     
         66 . The method of  claim 58  wherein the pharmaceutical composition is formulated for administration before the onset of an injury, disease, or condition. 
     
     
         67 . A method for protecting, maintaining, enhancing or restoring the function or viability of an erythropoietin-responsive mammalian cell, or its associated cells, tissues, or organs, comprising administering to a mammal a pharmaceutical composition comprising a therapeutically effective amount of an erythropoietin having at least one of the following modifications:
 i) 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 sialic acid moieties;   ii) a reduced number or no N-linked carbohydrates;   iii) one or more modified lysine residues; or   
       iv) a modification of the N-terminal amino group of the erythropoietin molecule, 
       wherein the modified erythropoietin has (a) tissue protective activity as determined in vitro by the P19 assay or in vivo by the middle cerebral artery lesion assay and (b) a reduced level of erythropoietic activity compared to native erythropoietin, and wherein said mammalian cell or its associated cells, tissues, or organs is heart, myocardium, or coronary artery. 
     
     
         68 . The method of  claim 67  wherein a lysine residue of said modified erythropoietin is carbamylated. 
     
     
         69 . The method of  claim 67  wherein said modified erythropoietin is asialoerythropoietin. 
     
     
         70 . The method of  claim 67  wherein said modified erythropoietin is non-erythropoietic. 
     
     
         71 . The method of  claim 67  wherein the mammal has, has had, is at risk for, or is undergoing, cardiac arrest, myocardial infarction, heart-lung bypass, heart injury, myocardium injury, heart trauma, chronic heart failure, or coronary artery occlusion. 
     
     
         72 . The method of  claim 67  wherein the pharmaceutical composition is formulated for administration before the onset of an injury, disease, or condition. 
     
     
         73 . A method for protecting, maintaining, enhancing or restoring the function or viability of an erythropoietin-responsive mammalian cell, or its associated cells, tissues, or organs, comprising administering to a mammal a pharmaceutical composition comprising a therapeutically effective amount of an erythropoietin having at least one of the following modifications:
 i) 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 sialic acid moieties;   ii) a reduced number or no N-linked carbohydrates;   iii) one or more modified lysine residues; or   iv) a modification of the N-terminal amino group of the erythropoietin molecule,   
       wherein the modified erythropoietin has (a) tissue protective activity as determined in vitro by the P19 assay or in vivo by the middle cerebral artery lesion assay and (b) a reduced level of erythropoietic activity compared to native erythropoietin, and wherein said mammalian cell or its associated cells, tissues, or organs is eye, retina, or kidney. 
     
     
         74 . The method of  claim 73  wherein a lysine residue of said modified erythropoietin is carbamylated. 
     
     
         75 . The method of  claim 73  wherein said modified erythropoietin is asialoerythropoietin. 
     
     
         76 . The method of  claim 73  wherein said modified erythropoietin is non-erythropoietic. 
     
     
         77 . The method of  claim 73  wherein the mammal has, has had, is at risk for, or is undergoing, eye tissue damage, macular degeneration, diabetic retinopathy, glaucoma, retinal ischemia, retinal trauma, retinitis pigmentosa, optic nerve damage, retinal detachment, arteriosclerotic retinopathy, hypertensive retinopathy, retinal artery blockage, retinal vein blockage, kidney injury, renal failure, ischemic renal failure, diabetic kidney disease, or a nephrotic syndrome. 
     
     
         78 . The method of  claim 73  wherein the pharmaceutical composition is formulated for administration before the onset of an injury, disease, or condition.