Compositions and methods for diagnosing and treating conditions, disorders, or diseases involving cell death

Abstract

The present invention relates to compositions and methods for the treatment and diagnosis of conditions, disorders, or diseases involving cell death. The invention encompasses protective nucleic acids which, when introduced into a cell predisposed to undergo cell death or in the process of undergoing cell death, prevent, delay, or rescue the cell from death relative to a corresponding cell into which no exogenous nucleic acids have been introduced. The invention encompasses nucleic acids of the protective sequence, host cell expression systems of the protective sequence, and hosts that have been transformed by these expression systems, including transgenic animals. The invention also encompasses novel protective sequence products, including proteins, polypeptides and peptides containing amino acid sequences of the proteins, fusion proteins of proteins, polypeptides and peptides, and antibodies directed against such gene products. The invention further relates to target sequences, including upstream and downstream regulatory sequences or complete gene sequences, antibodies, antisense molecules or sequences, ribozyme molecules, and other inhibitors or modulators directed against such protective sequences, protective sequence products, genes, gene products, and/or their regulatory elements involved in cell death. The present invention also relates to methods and compositions for the diagnosis and treatment of conditions, disorders, or diseases, involving cell death, including, but not limited to, treatment of the types of conditions, disorders, or diseases, which can be prevented, delayed or rescued from cell death and include, but are not limited to, those associated with the central nervous system, including neurological and psychiatric conditions, disorders, or diseases, and those of the peripheral nervous system. Further, the invention relates to methods of using the protective sequence, protective sequence products, and/or their regulatory elements for the identification of compounds that modulate the expression of the protective sequence and/or the activity of the protective sequence product. Such compounds can be useful as therapeutic agents in the treatment of various conditions, disorders, or diseases involving cell death.

What is claimed is:  
     
         1 . An isolated nucleic acid molecule comprising a nucleotide sequence that encodes a protective sequence product comprising: 
 (a) an amino acid sequence shown in FIGS.  4 (A-L);    (b) an amino acid sequence shown in FIGS.  5 (A-X);    (c) an amino acid sequence shown in FIGS.  6 (A-AD);    (d) an amino acid sequence shown in FIGS.  7 (A-H);    (e) an amino acid sequence shown in FIGS.  8 (A-O);    (f) an amino acid sequence shown in FIGS.  9 (A-AL);    (g) an amino acid sequence shown in FIGS.  10 (A-O);    (h) an amino acid sequence shown in FIGS.  11 (A-AG);    (i) an amino acid sequence shown in FIGS.  12 (A-AY); or    (j) the amino acid sequence shown in FIG. 13.    
     
     
         2 . An isolated nucleic acid molecule comprising: 
 (a) a nucleic acid shown in FIGS.  4 (A-L);    (b) a nucleic acid shown in FIGS.  5 (A-X);    (c) a nucleic acid shown in FIGS.  6 (A-AD);    (d) a nucleic acid shown in FIGS.  7 (A-H);    (e) a nucleic acid shown in FIGS.  8 (A-O);    (f) a nucleic acid shown in FIGS.  9 (A-AL);    (g) a nucleic acid shown in FIGS.  10 (A-O);    (h) a nucleic acid shown in FIGS.  11 (A-AG);    (i) a nucleic acid shown in FIGS.  12 (A-AY);    (j) a nucleic acid shown in FIG. 13; or    (k) a nucleic acid shown in FIGS.  1 (A-J);    
     
     
         3 . An isolated nucleic acid molecule comprising a complement of the nucleic acid molecule of any one of claims  1 - 2 .  
     
     
         4 . An isolated nucleic acid molecule which hybridizes to the complement of the nucleic acid molecule of any one of claims  1 - 2  under highly stringent conditions.  
     
     
         5 . An isolated nucleic acid molecule which hybridizes to the complement of the nucleic acid molecule of any one of claims  1 - 2  under moderately stringent conditions.  
     
     
         6 . The isolated nucleic acid molecule of  claim 4 , wherein said isolated nucleic acid molecule encodes a protective sequence product.  
     
     
         7 . The isolated nucleic acid molecule of  claim 5 , wherein said isolated nucleic acid molecule encodes a protective sequence product.  
     
     
         8 . A vector comprising the nucleic acid of any one of claims  1 - 2 .  
     
     
         9 . The vector of  claim 8 , wherein said vector is a viral vector.  
     
     
         10 . An expression vector comprising the nucleic acid of any one of claims  1 - 2  operatively associated with a regulatory nucleic acid controlling the expression of the nucleic acid in a host cell.  
     
     
         11 . A host cell genetically engineered to contain the nucleic acid of any one of claims  1 - 2 .  
     
     
         12 . A host cell genetically engineered to express the nucleic acid of any one of claims  1 - 2  operatively associated with a regulatory nucleic acid controlling expression of the nucleic acid in said host cell.  
     
     
         13 . A transgenic, non-human animal which has been genetically engineered to contain a transgene comprising the nucleic acid of any one of claims  1 - 2 .  
     
     
         14 . The transgenic, non-human animal of  claim 13 , wherein the transgene is expressed.  
     
     
         15 . An isolated polypeptide comprising the amino acid sequence of a protective sequence product comprising: 
 (a) an amino acid sequence shown in FIGS.  4 (A-L);    (b) an amino acid sequence shown in FIGS.  5 (A-X);    (c) an amino acid sequence shown in FIGS.  6 (A-AD);    (d) an amino acid sequence shown in FIGS.  7 (A-H);    (e) an amino acid sequence shown in FIGS.  8 (A-O);    (f) an amino acid sequence shown in FIGS.  9 (A-AL);    (g) an amino acid sequence shown in FIGS.  10 (A-O);    (h) an amino acid sequence shown in FIGS.  11 (A-AG);    (i) an amino acid sequence shown in FIGS.  12 (A-AY); or    (j) the amino acid sequence shown in FIG. 13.    
     
     
         16 . An isolated polypeptide comprising an amino acid sequence encoded by the isolated nucleic acid molecule of  claim 4 .  
     
     
         17 . An isolated polypeptide comprising an amino acid sequence encoded by the isolated nucleic acid molecule of  claim 5 .  
     
     
         18 . An isolated fusion polypeptide comprising a fusion peptide and an amino acid sequence of a protective sequence product comprising: 
 (a) an amino acid sequence shown in FIGS.  4 (A-L);    (b) an amino acid sequence shown in FIGS.  5 (A-X);    (c) an amino acid sequence shown in FIGS.  6 (A-AD);    (d) an amino acid sequence shown in FIGS.  7 (A-H);    (e) an amino acid sequence shown in FIGS.  8 (A-O);    (f) an amino acid sequence shown in FIGS.  9 (A-AL);    (g) an amino acid sequence shown in FIGS.  10 (A-O);    (h) an amino acid sequence shown in FIGS.  11 (A-AG);    (i) an amino acid sequence shown in FIGS.  12 (A-AY); or    (j) the amino acid sequence shown in FIG. 13.    
     
     
         19 . An isolated fusion polypeptide comprising a fusion peptide and an amino acid sequence encoded by the isolated nucleic acid molecule of  claim 4 .  
     
     
         20 . An isolated fusion polypeptide comprising a fusion peptide and an amino acid sequence encoded by the isolated nucleic acid molecules of  claim 5 .  
     
     
         21 . An antibody which binds to the isolated polypeptide of  claim 15 .  
     
     
         22 . A method for treating a protective sequence-mediated condition, disorder or disease in an individual comprising administering to the individual a compound which modulates the function, activity and/or expression of a protective sequence in a cell, cells, tissue, organ, organism or individual.  
     
     
         23 . The method of  claim 22 , wherein the compound inhibits or potentiates the function, activity and/or expression of a protective sequence in a cell, cells, tissue, organ, organism or individual.  
     
     
         24 . The method of  claim 22 , wherein the compound enhances or increases the function, activity and/or expression of a protective sequence in a cell, cells, tissue, organ, organism or individual.  
     
     
         25 . The methods of any one of claims  22 - 24 , wherein the compound is selected from the group consisting of a small organic molecule, an antibody, a ribozyme or an antisense molecule.  
     
     
         26 . The methods of any one of claims  22 - 24 , wherein the protective sequence-mediated condition, disorder, or disease is a condition, disorder, or disease of the central nervous system, including but not limited to, neurological and psychiatric conditions, disorders, or diseases.  
     
     
         27 . The method of  claim 26 , wherein the neurological condition is an ischemia-related condition.  
     
     
         28 . The method of  claim 27 , wherein the neurological condition is a stroke.  
     
     
         29 . The method of  claim 22 , wherein the protective sequence encodes a protective sequence product comprising: 
 (a) an amino acid sequence shown in FIGS.  4 (A-L);    (b) an amino acid sequence shown in FIGS.  5 (A-X);    (c) an amino acid sequence shown in FIGS.  6 (A-AD);    (d) an amino acid sequence shown in FIGS.  7 (A-H);    (e) an amino acid sequence shown in FIGS.  8 (A-O);    (d) an amino acid sequence shown in FIGS.  9 (A-AL);    (g) an amino acid sequence shown in FIGS.  10 (A-O);    (h) an amino acid sequence shown in FIGS.  11 (A-AG);    (i) an amino acid sequence shown in FIGS.  12 (A-AY); or    (j) the amino acid sequence shown in FIG. 13.    
     
     
         30 . The method of  claim 22 , wherein the individual is a mammal.  
     
     
         31 . The method of  claim 30 , wherein the mammal is a human.  
     
     
         32 . A method for treating a protective sequence-mediated condition, disorder or disease in an individual comprising administering to the individual a compound which modulates the expression or activity of a protective sequence product and/or protective sequence regulatory product in the individual.  
     
     
         33 . The method of  claim 32 , wherein the compound inhibits or potentiates the expression or activity of a protective sequence product and/or protective sequence regulatory product in the individual.  
     
     
         34 . The method of  claim 32 , wherein the compound enhances or increases the expression or activity of a protective sequence product and/or protective sequence regulatory product in the individual.  
     
     
         35 . The method of  claim 32 , wherein the compound is selected from the group consisting of a small organic molecule, an antibody, a ribozyme.or an antisense molecule.  
     
     
         36 . The method of  claim 32 , wherein the protective sequence-mediated condition, disorder, or disease is a condition, disorder, or disease of the central nervous system, including but not limited to, neurological and psychiatric conditions, disorders, or diseases.  
     
     
         37 . The method of  claim 36 , wherein the neurological condition is an ischemia-related condition.  
     
     
         38 . The method of  claim 37 , wherein the neurological condition is a stroke.  
     
     
         39 . The method of  claim 32 , wherein the protective sequence product comprises: 
 (a) an amino acid sequence shown in FIGS.  4 (A-L);    (b) an amino acid sequence shown in FIGS.  5 (A-X);    (c) an amino acid sequence shown in FIGS.  6 (A-AD);    (d) an amino acid sequence shown in FIGS.  7 (A-H);    (e) an amino acid sequence shown in FIGS.  8 (A-O);    (f) an amino acid sequence shown in FIGS.  9 (A-AL);    (g) an amino acid sequence shown in FIGS.  10 (A-O);    (h) an amino acid sequence shown in FIGS.  11 (A-AG);    (i) an amino acid sequence shown in FIGS.  12 (A-AY); or    (j) the amino acid sequence shown in FIG. 13.    
     
     
         40 . The method of  claim 32 , wherein the individual is a mammal.  
     
     
         41 . The method of  claim 40 , wherein the mammal is a human.  
     
     
         42 . A method for identifying a compound which modulates expression of a protective sequence comprising: 
 (a) contacting a test compound to a cell that expresses a protective sequence;    (b) measuring a level of protective sequence expression in the cell;    (c) comparing the level of protective sequence expression in the cell in the presence of the test compound to a level of protective sequence expression in the cell in the absence of the test compound,    wherein if the level of protective sequence expression in the cell in the presence of the test compound differs from the level of expression of the protective sequence in the cell in the absence of the test compound, a compound that modulates expression of a protective sequence is identified.    
     
     
         43 . The method of  claim 42 , wherein the protective sequence is endogenously expressed within the cell.  
     
     
         44 . The method of  claim 42 , wherein the protective sequence encodes a protective sequence product comprising: 
 (a) an amino acid sequence shown in FIGS.  4 (A-L);    (b) an amino acid sequence shown in FIGS.  5 (A-X);    (c) an amino acid sequence shown in FIGS.  6 (A-AD);    (d) an amino acid sequence shown in FIGS.  7 (A-H);    (e) an amino acid sequence shown in FIGS.  8 (A-O);    (f) an amino acid sequence shown in FIGS.  9 (A-AL);    (g) an amino acid sequence shown in FIGS.  10 (A-O);    (h) an amino acid sequence shown in FIGS.  11 (A-AG);    (i) an amino acid sequence shown in FIGS.  12 (A-AY); or    (j) the amino acid sequence shown in FIG. 13.    
     
     
         45 . The method of  claim 42 , wherein the protective sequence comprises: 
 (a) a nucleic acid shown in FIGS.  4 (A-L);    (b) a nucleic acid shown in FIGS.  5 (A-X);    (c) a nucleic acid shown in FIGS.  6 (A-AD);    (d) a nucleic acid shown in FIGS.  7 (A-H);    (e) a nucleic acid shown in FIGS.  8 (A-O);    (f) a nucleic acid shown in FIGS.  9 (A-AL);    (g) a nucleic acid shown in FIGS.  10 (A-O);    (h) a nucleic acid shown in FIGS.  11 (A-AG);    (i) a nucleic acid shown in FIGS.  12 (A-AY);    (j) a nucleic acid shown in FIG. 13; or    (k) a nucleic acid shown in FIGS.  1 (A-J);    
     
     
         46 . A method for identifying a compound which modulates expression, function or activity of a protective sequence product or protective sequence regulatory element comprising: 
 (a) contacting a test compound to a cell that expresses a protective sequence product or protective sequence regulatory element;    (b) measuring a level of protective sequence product or protective sequence regulatory element expression, function or activity in the cell;    (c) comparing the level of protective sequence product or protective sequence regulatory element expression, function or activity in the cell in the presence of the test compound to a level of protective sequence product or protective sequence regulatory element expression or activity in the cell in the absence of the test compound,    wherein if the level of protective sequence product or protective sequence regulatory element expression, function or activity in the cell in the presence of the test compound differs from the level of protective sequence product or protective sequence regulatory element expression, function or activity in the cell in the absence of the test compound, a compound that modulates expression or activity of a protective sequence product or protective sequence regulatory element is identified.    
     
     
         47 . The method of  claim 46 , wherein the protective sequence product or protective sequence regulatory element comprises: 
 (a) an amino acid sequence shown in FIGS.  4 (A-L);    (b) an amino acid sequence shown in FIGS.  5 (A-X);    (c) an amino acid sequence shown in FIGS.  6 (A-AD);    (d) an amino acid sequence shown in FIGS.  7 (A-H);    (e) an amino acid sequence shown in FIGS.  8 (A-O);    (f) an amino acid sequence shown in FIGS.  9 (A-AL);    (g) an amino acid sequence shown in FIGS.  10 (A-O);    (h) an amino acid sequence shown in FIGS.  11 (A-AG);    (i) an amino acid sequence shown in FIGS.  12 (A-AY); or    (j) the amino acid sequence shown in FIG. 13.    
     
     
         48 . A method for transferring a protective sequence into a cell comprising contacting the cell with a nucleic acid comprising a protective sequence such that the protective sequence is transferred into the cell.  
     
     
         49 . The method of  claim 48  wherein the protective sequence is expressed in the cell.  
     
     
         50 . The method of  claim 48  wherein the protective sequence confers protection to the cell from cell death.  
     
     
         51 . A method for modulating the function, activity and/or expression of a protective sequence in a cell comprising administering to the cell a compound which modulates the function, activity and/or expression of a protective sequence in the cell.  
     
     
         52 . The method of  claim 51 , wherein the compound inhibits or potentiates the function, activity and/or expression of a protective sequence in the cell.  
     
     
         53 . The method of  claim 51 , wherein the compound enhances or increases the function, activity and/or expression of a protective sequence in the cell.  
     
     
         54 . The methods of any one of claims  51 - 53 , wherein the compound is selected from the group consisting of a small organic molecule, an antibody, a ribozyme.or an antisense molecule.  
     
     
         55 . The method of  claim 51 , wherein the protective sequence encodes a protective sequence product comprising: 
 (a) an amino acid sequence shown in FIGS.  4 (A-L);    (b) an amino acid sequence shown in FIGS.  5 (A-X);    (c) an amino acid sequence shown in FIGS.  6 (A-AD);    (d) an amino acid sequence shown in FIGS.  7 (A-H);    (e) an amino acid sequence shown in FIGS.  8 (A-O);    (f) an amino acid sequence shown in FIGS.  9 (A-AL);    (g) an amino acid sequence shown in FIGS.  10 (A-O);    (h) an amino acid sequence shown in FIGS.  11 (A-AG);    (i) an amino acid sequence shown in FIGS.  12 (A-AY); or    (j) the amino acid sequence shown in FIG. 13.