Compositions and methods for altering cell migration

Abstract

The invention relates generally to compositions useful in altering the migration and/or proliferative activity of cells and to methods of using them. Reagents that can regulate cell migration and reorganization are useful in managing diseases in which cell migration and tissue remodeling play a role, including inhibiting vascular stenosis and restenosis that can result from endothelial injury. Migration-altering compositions include the proteins clusterin and gp38k and fragments thereof which retain the migration-altering activity, peptides derived from the proteins which possess the migration-altering activity, polyclonal, monoclonal and recombinant humanized antibodies directed against the proteins and fragments thereof and anti-sense oligonucleotides capable of binding clusterin and gp38k mRNAs.

1 . A gp38K-related peptide selected from T-L-L-S-V-G-G-W-N-F-G-S-Q-R, R-T-H-G-F-D-G-L-D-L-A, P-G-R-R-D-R-R-H-L-T-T-L-V-K-E-M, V-A-I-D-R-G-Y-D-I-A-Q-I-S-Q-H-L-D-F-I, F-G-R-S-F-T-L-A-S-S-K-T-D, and N-L-R-F-P-L-T-S-A-I-K-D and analogs thereof containing functionally equivalent amino acids.  
     
     
         2 . The gp38K-related peptide according to  claim 1  wherein up to three amino acids are substituted for functionally equivalent amino acids.  
     
     
         3 . The gp38K-related peptide according to  claim 1  wherein up to two amino acids are substituted for functionally equivalent amino acids.  
     
     
         4 . A compound, according to  claim 1 , of formula T-L-L-S-V-G-G-W-N-F-G-S-Q-R, or pharmaceutically acceptable salt thereof, wherein any amino acid can be replaced by a functionally equivalent amino acid.  
     
     
         5 . A compound, according to  claim 1 , of formula R-T-H-G-F-D-G-L-D-L-A, or pharmaceutically acceptable salt thereof, wherein any amino acid can be replaced by a functionally equivalent amino acid.  
     
     
         6 . A compound, according to  claim 1 , of formula P-G-R-R-D-R-R-H-L-T-T-L-V-K-E-M, or pharmaceutically acceptable salt thereof, wherein any amino acid can be replaced by a functionally equivalent amino acid.  
     
     
         7 . A compound, according to  claim 1 , of formula V-A-I-D-R-G-Y-D-I-A-Q-I-S-Q-H-L-D-F-I, or pharmaceutically acceptable salt thereof, wherein any amino acid can be replaced by a functionally equivalent amino acid.  
     
     
         8 . A compound, according to  claim 1 , of formula F-G-R-S-F-T-L-A-S-S-K-T-D, or pharmaceutically acceptable salt thereof, wherein any amino acid can be replaced by a functionally equivalent amino acid.  
     
     
         9 . A compound, according to  claim 1 , of formula N-L-R-F-P-L-T-S-A-I-K-D, or pharmaceutically acceptable salt thereof, wherein any amino acid can be replaced by a functionally equivalent amino acid.  
     
     
         10 . A clusterin-related peptide chosen from D-K-A-I-S-D-K-E-L-Q-E-M-S-T-E-G-S-K-Y-V, L-W-E-E-C-K-P-C-L-K-Q-T-C, K-Q-L-N-E-Q-F-S-W-V-S-Q-L-A, L-M-E-N-D-R-Q-Q-S-H-V-M-D-I-M-E-D, and K-Q-T-C-M-K-F-Y-A-R-V-C-R-S-G, and analogs thereof containing functionally equivalent amino acids.  
     
     
         11 . The clusterin-related peptide according to  claim 10  wherein up to three amino acids are substituted for functionally equivalent amino acids.  
     
     
         12 . The clusterin-related peptide according to  claim 10  wherein up to two amino acids are substituted for functionally equivalent amino acids.  
     
     
         13 . A compound, according to  claim 10 , of formula D-K-A-I-S-D-K-E-L-Q-E-M-S-T-E-G-S-K-Y-V or pharmaceutically acceptable salt thereof, wherein any amino acid can be replaced by a functionally equivalent amino acid.  
     
     
         14 . A compound, according to  claim 10 , of formula L-W-E-E-C-K-P-C-L-K-Q-T-C or pharmaceutically acceptable salt thereof, wherein any amino acid can be replaced by a functionally equivalent amino acid.  
     
     
         15 . A compound, according to  claim 10 , of formula L-M-E-N-D-R-Q-Q-S-H-V-M-D-I-M-E-D, or pharmaceutically acceptable salt thereof, wherein any amino acid can be replaced by a functionally equivalent amino acid.  
     
     
         16 . A compound, according to  claim 10 , of formula K-Q-L-N-E-Q-F-S-W-V-S-Q-L-A, or pharmaceutically acceptable salt thereof, wherein any amino acid can be replaced by a functionally equivalent amino acid.  
     
     
         17 . A compound, according to  claim 10 , of formula K-Q-T-C-M-K-F-Y-A-R-V-C-R-S-G, or pharmaceutically acceptable salt thereof, wherein any amino acid can be replaced by a functionally equivalent amino acid.  
     
     
         18 . A DNA sequence which codes for an RNA that is complementary to and capable of binding to a transcribed sequence of clusterin.  
     
     
         19 . A DNA sequence which codes for an RNA that is complementary to and capable of binding to a transcribed sequence of gp38K.  
     
     
         20 . A method of altering cell migration by contacting said cells with a migration-altering composition derived from clusterin or gp38K.  
     
     
         21 . A method of treatment for a disease or condition associated with cell migration comprising administering to a patient in need of such treatment a therapeutically effective amount of a migration-altering composition derived from clusterin or gp38K.  
     
     
         22 . The method of  claim 21 , wherein said migration-altering composition is an antibody which inhibits the chemotactic or mitotic activity of clusterin or gp38K.  
     
     
         23 . The method of  claim 22 , wherein said antibody is selected from antibodies to clusterin, antibodies to clusterin fragments, antibodies to clusterin peptides, antibodies to gp38K, antibodies to gp38K fragments, antibodies to gp38K peptides and a combination thereof.  
     
     
         24 . The method of  claim 21  wherein said disease or condition is restenosis or atherosclerosis.  
     
     
         25 . The method of  claim 21  wherein said treatment is for tumor suppression.  
     
     
         26 . The method of  claim 21  wherein said migration-altering composition is a DNA sequence which codes for an RNA that is complementary to and capable of binding to a transcribed sequence of gp38K, and wherein said migration-altering composition inhibits the chemotactic or mitotic activity of gp38K.  
     
     
         27 . The method of  claim 21 , wherein said migration-altering composition is a DNA sequence which codes for an RNA that is complementary to and capable of binding to a transcribed sequence of clusterin, and wherein said migration-altering composition inhibits the chemotactic or mitotic activity of clusterin.  
     
     
         28 . A method of inducing cell migration in a patient in need of such therapy by administering to the patient a therapeutically effective amount of a migration-inducing composition derived from clusterin or gp38K.  
     
     
         29 . The method of  claim 28 , wherein said migration-inducing composition is selected from clusterin, clusterin fragments, clusterin peptides and analogs thereof, gp38K, gp38K fragments, gp38K peptides and analogs thereof, and a combination thereof.  
     
     
         30 . The method of  claim 28 , wherein said induction of cell migration is to facilitate angiogenesis or wound healing.