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 . Use of an erythropoietin selected from the group consisting of
 i) an erythropoietin having at least no sialic acid moieties;   ii) an erythropoietin having at least no N-linked or no O-linked carbohydrates;   iii) an erythropoietin having at least a reduced carbohydrate content by virtue of treatment of native erythropoietin with at least one glycosidase;   iv) an erythropoietin with a carbohydrate portion of the erythropoietin molecule having at least a non-mammalian glycosylation pattern by virtue of the expression of a recombinant erythropoietin in non-mammalian cells;   v) an erythropoietin has at least one or more oxidized carbohydrates which also may be chemically reduced;   vi) an erythropoietin having at least one or more modified arginine residues;   vii) an erythropoietin having at least one or more modified lysine residues or a modification of the N-terminal amino group of the erythropoietin molecule;   viii) an erythropoietin having at least a modified tyrosine residue;   ix) an erythropoietin having at least a modified aspartic acid or a glutamic acid residue;   x) an erythropoietin having at least a modified tryptophan residue;   xi) an erythropoietin having at least one amino group removed;   xii) an erythropoietin having at least an opening of at least one of the cystine linkages in the erythropoietin molecule;   xiii) an erythropoietin is provided having at least one substitution of at least one amino acid; and   xiv) a truncated erythropoietin;   
       for the preparation of a pharmaceutical composition for protecting, maintaining, enhancing or restoring the function or viability of erythropoietin-responsive mammalian cells and their associated cells, tissues and organs. 
     
     
         2 . The use of  claim 1  wherein said erythropoietin is asialoerythropoietin. 
     
     
         3 . The use of  claim 2  wherein said asialoerythropoietin is human asialoerythropoietin. 
     
     
         4 .- 16 . (canceled) 
     
     
         17 . The use of  claim 1  wherein a lysine residue of said erythropoietin is carbamylated. 
     
     
         18 . The use of  claim 1  wherein a lysine residue of said erythropoietin is acylated. 
     
     
         19 . The use of  claim 18  wherein a lysine residue of said erythropoietin is acetylated. 
     
     
         20 . The use of  claim 18  wherein a lysine residue of said erythropoietin is succinylated 
     
     
         21 .- 24 . (canceled) 
     
     
         25 . The use of  claim 1  wherein the erythropoietin-responsive cells or tissues are neuronal, retinal, muscle, heart, lung, liver, kidney, small intestine, adrenal cortex, adrenal medulla, capillary endothelial, testes, ovary, or endometrial cells or tissue. 
     
     
         26 . A pharmaceutical composition comprising an effective erythropoietin-responsive cell protecting, maintaining, enhancing, or restoring amount of an erythropoietin selected from the group consisting of
 i) an erythropoietin having at least no sialic acid moieties;   ii) an erythropoietin having at least no N-linked or no O-linked carbohydrates;   iii) an erythropoietin having at least a reduced carbohydrate content by virtue of treatment of native erythropoietin with at least one glycosidase;   iv) an erythropoietin with a carbohydrate portion of the erythropoietin molecule having at least a non-mammalian glycosylation pattern by virtue of the expression of a recombinant erythropoietin in non-mammalian cells;   v) an erythropoietin has at least one or more oxidized carbohydrates which also may be chemically reduced;   vi) an erythropoietin having at least one or more modified arginine residues;   vii) an erythropoietin having at least one or more modified lysine residues or a modification of the N-terminal amino group of the erythropoietin molecule;   viii) an erythropoietin having at least a modified tyrosine residue;   ix) an erythropoietin having at least a modified aspartic acid or a glutamic acid residue;   x) an erythropoietin having at least a modified tryptophan residue;   xi) an erythropoietin having at least one amino group removed;   xii) an erythropoietin having at least an opening of at least one of the cystine linkages in the erythropoietin molecule;   xiii) an erythropoietin is provided having at least one substitution of at least one amino acid; and   xiv) a truncated erythropoietin.   
     
     
         27 . (canceled) 
     
     
         28 . Use of an erythropoietin for the preparation of a pharmaceutical composition for protecting, maintaining, enhancing or restoring the function or viability of an erythropoietin-responsive cell or its associated cells, tissues, or organs, wherein said cells, tissues, or organs are not excitable cells, tissues, or organs, or do not predominantly comprise excitable cells or tissues. 
     
     
         29 . The use of  claim 28  wherein said erythropoietin is an erythropoietin or native erythropoietin, or an erythropoietin analog, an erythropoietin mimetic, an erythropoietin. fragment, a hybrid erythropoietin molecule, an erythropoietin-receptor-binding molecule, an erythropoietin agonist, a renal erythropoietin, a brain erythropoietin, an oligomer thereof, a multimer thereof, a mutein thereof, a congener thereof, a naturally-occurring form thereof, a synthetic form thereof, a recombinant form thereof, a glycosylation variant thereof, a deglycosylated variant thereof, or a combination thereof. 
     
     
         30 .- 35 . (canceled) 
     
     
         36 . Use of an erythropoietin selected from the group consisting of an erythropoietin or native erythropoietin, or an erythropoietin analog, an erythropoietin mimetic, an erythropoietin fragment, a hybrid erythropoietin molecule, an erythropoietin-receptor-binding molecule, an erythropoietin agonist, a renal erythropoietin, a brain erythropoietin, an oligomer thereof, a multimer thereof, a mutein thereof, a congener thereof, a naturally occurring form thereof, a synthetic form thereof, a recombinant form thereof, a glycosylation variant thereof, a deglycosylated variant thereof, or a combination thereof for the preparation of a pharmaceutical composition for the restoration of cognitive function in a mammal having or at risk for cognitive dysfunction. 
     
     
         37 . The use of  claim 36  wherein the cognitive dysfunction is the result of injury caused by a seizure disorder, multiple sclerosis, stroke, hypotension, cardiac arrest, ischemia, myocardial infarction, inflammation, age-related loss of cognitive function, radiation damage, cerebral palsy, neurodegenerative disease, Alzheimer's disease, Parkinson's disease, Leigh disease, AIDS dementia, memory loss, amyotrophic lateral sclerosis, alcoholism, mood disorder, anxiety disorder, attention deficit disorder, autism, Creutzfeld-Jakob disease, brain or spinal cord trauma or ischemia, heart-lung bypass, chronic heart failure, macular degeneration, diabetic neuropathy, diabetic retinopathy, glaucoma, retinal ischemia, or retinal trauma. 
     
     
         38 . (canceled) 
     
     
         39 . The use of  claim 36  wherein said erythropoietin is
 (i) an erythropoietin having at least no sialic acid moieties; 
 (ii) an erythropoietin having at least no N-linked or no O-linked carbohydrates; 
 (iii) an erythropoietin having at least a reduced carbohydrate content by virtue of treatment of native erythropoietin with at least one glycosidase; 
 (iv) an erythropoietin with a carbohydrate portion of the erythropoietin molecule having at least a non-mammalian glycosylation pattern by virtue of the expression of a recombinant erythropoietin in non-mammalian cells; 
 (v) an erythropoietin has at least one or more oxidized carbohydrates which also may be chemically reduced; 
 (vi) an erythropoietin having at least one or more modified arginine residues; 
 (vii) an erythropoietin having at least one or more modified lysine residues or a modification of the N-terminal amino group of the erythropoietin molecule; 
 (viii) an erythropoietin having at least a modified tyrosine residue; 
 (ix) an erythropoietin having at least a modified aspartic acid or a glutamic acid residue; 
 (x) an erythropoietin having at least a modified tryptophan residue; 
 (xi) an erythropoietin having at least one amino group removed; 
 (xii) an erythropoietin having at least an opening of at least one of the cystine linkages in the erythropoietin molecule; 
 (xiii) an erythropoietin is provided having at least one substitution of at least one amino acid; or 
 (xiv) a truncated erythropoietin. 
 
     
     
         40 .- 57 . (canceled)